Gene products differentially expressed in cancerous cells III

ABSTRACT

The present invention provides polynucleotides, as well as polypeptides encoded thereby, that are differentially expressed in cancer cells. These polynucleotides are useful in a variety of diagnostic and therapeutic methods. The present invention further provides methods of reducing growth of cancer cells. These methods are useful for treating cancer.

SEQUENCE LISTING AND TABLES

A Sequence Listing is provided as part of this specification on triplicate compact discs, filed concurrently herewith, which compact discs named “Copy 1”, “Copy 2”, and “CRF” each of which compact discs contain the following file: “SEQLIST.TXT”, created Sep. 7, 2004, of 8693 kilobytes, which is incorporated herein by reference in its entirety.

The present application also incorporates by reference Tables 6, 15, 16, 31, 33, 34, and 35 contained on duplicate compact discs filed concurrently herewith, which compact discs are labeled “Atty Docket 2300-21987 Tables Copy 1” and “Atty Docket 2300-21987 Tables Copy 2”. The details of these Tables are further described later in this disclosure. These compact discs were created on Sep. 7th, 2004. The sizes of the Tables are as follows: Table 6: 70 kilobytes; Table 15: 254 kilobytes; Table 16: 407 kilobytes; Table 31: 603 kilobytes; Table 33: 379 kilobytes; Table 34: 985 kilobytes; and Table 35: 518 kilobytes. LENGTHY TABLES FILED ON CD The patent application contains a lengthy table section. A copy of the table is available in electronic form from the USPTO web site (http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20070010469A1) An electronic copy of the table will also be available from the USPTO upon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

FIELD OF THE INVENTION

The present invention relates to polynucleotides of human origin in substantially isolated form and gene products that are differentially expressed in cancer cells, and uses thereof.

BACKGROUND OF THE INVENTION

Cancer, like many diseases, is not the result of a single, well-defined cause, but rather can be viewed as several diseases, each caused by different aberrations in informational pathways, that ultimately result in apparently similar pathologic phenotypes. Identification of polynucleotides that correspond to genes that are differentially expressed in cancerous, pre-cancerous, or low metastatic potential cells relative to normal cells of the same tissue type, provides the basis for diagnostic tools, facilitates drug discovery by providing for targets for candidate agents, and further serves to identify therapeutic targets for cancer therapies that are more tailored for the type of cancer to be treated.

Identification of differentially expressed gene products also furthers the understanding of the progression and nature of complex diseases such as cancer, and is key to identifying the genetic factors that are responsible for the phenotypes associated with development of, for example, the metastatic phenotype. Identification of gene products that are differentially expressed at various stages, and in various types of cancers, can both provide for early diagnostic tests, and further serve as therapeutic targets. Additionally, the product of a differentially expressed gene can be the basis for screening assays to identify chemotherapeutic agents that modulate its activity (e.g. its expression, biological activity, and the like).

Early disease diagnosis is of central importance to halting disease progression, and reducing morbidity. Analysis of a patient's tumor to identify the gene products that are differentially expressed, and administration of therapeutic agent(s) designed to modulate the activity of those differentially expressed gene products, provides the basis for more specific, rational cancer therapy that may result in diminished adverse side effects relative to conventional therapies. Furthermore, confirmation that a tumor poses less risk to the patient (e.g., that the tumor is benign) can avoid unnecessary therapies. In short, identification of genes and the encoded gene products that are differentially expressed in cancerous cells can provide the basis of therapeutics, diagnostics, prognostics, therametrics, and the like.

For example, breast cancer is a leading cause of death among women. One of the priorities in breast cancer research is the discovery of new biochemical markers that can be used for diagnosis, prognosis and monitoring of breast cancer. The prognostic usefulness of these markers depends on the ability of the marker to distinguish between patients with breast cancer who require aggressive therapeutic treatment and patients who should be monitored.

While the pathogenesis of breast cancer is unclear, transformation of non-tumorigenic breast epithelium to a malignant phenotype may be the result of genetic factors, especially in women under 30 (Miki, et al., Science, 266: 66-71, 1994).

However, it is likely that other, non-genetic factors are also significant in the etiology of the disease. Regardless of its origin, breast cancer morbidity increases significantly if a lesion is not detected early in its progression. Thus, considerable effort has focused on the elucidation of early cellular events surrounding transformation in breast tissue. Such effort has led to the identification of several potential breast cancer markers.

Thus, the identification of new markers associated with cancer, for example, breast cancer, and the identification of genes involved in transforming cells into the cancerous phenotype, remains a significant goal in the management of this disease. In exemplary aspects, the invention described herein provides cancer diagnostics, prognostics, therametrics, and therapeutics based upon polynucleotides and/or their encoded gene products.

SUMMARY OF THE INVENTION

The present invention provides methods and compositions useful in detection of cancerous cells, identification of agents that modulate the phenotype of cancerous cells, and identification of therapeutic targets for chemotherapy of cancerous cells. Cancerous prostate cells are of particular interest in each of these aspects of the invention. More specifically, the invention provides polynucleotides, as well as polypeptides encoded thereby, that are differentially expressed in prostate cancer cells. Also provided are antibodies that specifically bind the encoded polypeptides. These polynucleotides, polypeptides and antibodies are thus useful in a variety of diagnostic, therapeutic, and drug discovery methods. In some embodiments, a polynucleotide that is differentially expressed in prostate cancer cells can be used in diagnostic assays to detect prostate cancer cells. In other embodiments, a polynucleotide that is differentially expressed in prostate cancer cells, and/or a polypeptide encoded thereby, is itself a target for therapeutic intervention.

Accordingly, in one aspect the invention provides a method for detecting a cancerous prostate cell. In general, the method involves contacting a test sample obtained from a cell that is suspected of being a prostate cancer cell with a probe for detecting a gene product differentially expressed in prostate cancer. Many embodiments of the invention involve a gene identifiable or comprising a sequence selected from the group consisting of SEQ ID NOS: 1-3996, contacting the probe and the gene product for a time sufficient for binding of the probe to the gene product; and comparing a level of binding of the probe to the sample with a level of probe binding to a control sample obtained from a control prostate cell of known cancerous state. A modulated (i.e. increased or decreased) level of binding of the probe in the test prostate cell sample relative to the level of binding in a control sample is indicative of the cancerous state of the test prostate cell. In certain embodiments, the level of binding of the probe in the test cell sample, usually in relation to at least one control gene, is similar to binding of the probe to a cancerous cell sample. In certain other embodiments, the level of binding of the probe in the test cell sample, usually in relation to at least one control gene, is different, i.e. opposite, to binding of the probe to a non-cancerous cell sample. In specific embodiments, the probe is a polynucleotide probe and the gene product is nucleic acid. In other specific embodiments, the gene product is a polypeptide. In further embodiments, the gene product or the probe is immobilized on an array.

In another aspect, the invention provides a method for assessing the cancerous phenotype (e.g., metastasis, metatstatic potential, aberrant cellular proliferation, and the like) of a prostate cell comprising detecting expression of a gene product in a test prostate cell sample, wherein the gene comprises a sequence selected from the group consisting of SEQ ID NOS: 1-13996; and comparing a level of expression of the gene product in the test prostate cell sample with a level of expression of the gene in a control cell sample. Comparison of the level of expression of the gene in the test cell sample relative to the level of expression in the control cell sample is indicative of the cancerous phenotype of the test cell sample. In specific embodiments, detection of gene expression is by detecting a level of an RNA transcript in the test cell sample. In other specific embodiments detection of expression of the gene is by detecting a level of a polypeptide in a test sample.

In another aspect, the invention provides a method for suppressing or inhibiting a cancerous phenotype of a cancerous cell, the method comprising introducing into a mammalian cell an expression modulatory agent (e.g. an antisense molecule, small molecule, antibody, neutralizing antibody, inhibitory RNA molecule, etc.) to inhibition of expression of a gene identified by a sequence selected from the group consisting of SEQ ID NOS: 1-13996. Inhibition of expression of the gene inhibits development of a cancerous phenotype in the cell. In specific embodiments, the cancerous phenotype is metastasis, aberrant cellular proliferation relative to a normal cell, or loss of contact inhibition of cell growth. In the context of this invention “expression” of a gene is intended to encompass the expression of an activity of a gene product, and, as such, inhibiting expression of a gene includes inhibiting the activity of a product of the gene.

In another aspect, the invention provides a method for assessing the tumor burden of a subject, the method comprising detecting a level of a differentially expressed gene product in a test sample from a subject suspected of or having a tumor, the differentially expressed gene product comprising a sequence selected from the group consisting of SEQ ID NOS: 1 -13996. Detection of the level of the gene product in the test sample is indicative of the tumor burden in the subject.

In another aspect, the invention provides a method for identifying a gene product as a target for a cancer therapeutic, the method comprising contacting a cancerous cell expressing a candidate gene product with an anti-cancer agent, wherein the candidate gene product corresponds to a sequence selected from the group consisting of SEQ ID NOS: 1-13996; and analyzing the effect of the anti-cancer agent upon a biological activity of the candidate gene product and/or upon a.cancerous phenotype of the cancerous cell. Modulation of the biological activity of the candidate gene product and modulation of the cancerous phenotype of the cancerous cell indicates the candidate gene product is a target for a cancer therapeutic. In specific embodiments, the cancerous cell is a cancerous prostate cell. In other specific embodiments, the inhibitor is an antisense oligonucleotide. In further embodiments, the cancerous phenotype is aberrant cellular proliferation relative to a normal cell, or colony formation due to loss of contact inhibition of cell growth.

In another aspect, the invention provides a method for identifying agents that modulate (i.e. increase or decrease) the biological activity of a gene product differentially expressed in a cancerous cell, the method comprising contacting a candidate agent with a differentially expressed gene product, the differentially expressed gene product corresponding to a sequence selected from the group consisting of SEQ ID NOS: 1-13996; and detecting a modulation in a biological activity of the gene product relative to a level of biological activity of the gene product in the absence of the candidate agent. In specific embodiments, the detecting is by identifying an increase or decrease in expression of the differentially expressed gene product. In other specific embodiments, the gene product is mRNA or cDNA prepared from the mRNA gene product. In further embodiments, the gene product is a polypeptide.

In another aspect, the invention provides a method of inhibiting growth of a tumor cell by modulating expression of a gene product, where the gene product is encoded by a gene identified by a sequence selected from the group consisting of: SEQ ID NOS:1-13996.

The invention provides a method of determining the cancerous state of a cell, comprising detecting a level of a product of a gene in a test cell wherein said gene is defined by a sequence selected from a group consisting of SEQ ID NOS: -1-3996 wherein the cancerous state of the test cell is indicated by detection of said level and comparison to a control level of said gene product. In certain embodiments of this method, the gene product is a nucleic acid or a polypeptide. In certain embodiments of this method, the gene product is immobilized on an array. In one embodiment of this method, the control level is a level of said gene product associated with a control cell of known cancerous state. In other embodiments of this method, the known cancerous state is a non-cancerous state. In another embodiment of this method, the level differs from the control level by at least two fold, indicating the test cell is not of the same cancerous state as that indicated by the control level.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a schematic showing the alignment of the sequences (represented by single lines) that resulted in the assembly of the contig (represented by the bars in the lower portion of the figure).

FIGS. 2-17 are graphs showing the expression profiles of the genes of Group 1.

FIGS. 18-21 are graphs showing the expression profiles of the genes of Group 2. In addition to the figures described above, the application also includes Tables 10-12, as well as a Sequence Listing.

FIG. 22 is a table showing the expression of condroitin 4-O sulfotransferase 2 (C4S-2) in cancer versus normal cells, as determined by microarray analysis.

FIG. 23 is a bar graph showing C4S-2 mRNA expression in laser capture microdissected tissues, as determined by quantitative PCR analysis.

FIG. 24 is a bar graph showing C4S-2 mRNA expression in tissue samples.

FIG. 25 is a bar graph showing C4S-2 mRNA expression in prostate cell lines.

FIG. 26 is a table of antisense polynucleotides, directed against C4S-2.

FIG. 27 is a table of inhibitory RNA polynucleotides, directed against C4S-2.

FIG. 28 is two line graphs showing the effect of C4S-2 antisense molecules on growth of PC3 cells.

FIG. 29 is a line graph showing the effect of C4S-2 antisense molecules on growth of MDA PCa 2b cells.

FIG. 30 is a bar graph showing the effects of C4S-2 antisense molecules on PC3 growth in soft-agar.

FIG. 31 is two line graphs showing the effects of C4S-2 antisense molecules on growth of MDA PCa 2b cells growth in soft-agar.

FIGS. 32A-D show the effects of C4S-2 antisense molecules on MDA PCa 2b spheroids. FIGS. 32A-C are photographs of spheroids. FIGS. 32D is a bar graph showing LDH ratios.

FIG. 33A-C show the effects of C4S-2 antisense molecules on MRC9 cells. FIG. 33A is a graph of cytotoxicity. FIG. 33B is a graph showing relative mRNA expression of C4S-2 in cell lines. FIG. 33C is a panel of photographs of MRC9 cells.

FIG. 34 is a three dimensional bar graph showing effects of C4S-2 antisense molecules on 184B5 cell cytotoxicity.

FIG. 35 is a composite of graphs showing effects of C4S-2 antisense molecules on 184B5 and MRC9 cell proliferation.

FIG. 36 is a table of genes that are co-regulated with C4S-2.

FIG. 37 is a sequence alignment of mouse C4S-2 (top) and human C4S-2 (bottom).

FIG. 38 is three panels of autoradiographs showing expression of GAK polypeptide in different cell lines.

FIG. 39 is a graph of a hydropathy plot and a table showing the hydrophobic regions of DKFZp566I 33.

FIG. 40 is six panels of photographs of MDA-231 cells exposed to C1 80-7, C180-8 and positive control antisense (AS) and control (RC) oligonucleotides.

FIG. 41 is an alignment of spot ID 22793 and spot ID 26883.

FIG. 42 is a figure of three sequence alignments showing the mapping of each of three sequences onto VMP1 (DKFZ).

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides polynucleotides, as well as polypeptides encoded thereby, that are differentially expressed in cancer cells. Methods are provided in which these polynucleotides and polypeptides are used for detecting and reducing the growth of cancer cells. Also provided are methods in which the polynucleotides and polypeptides of the invention are used in a variety of diagnostic and therapeutic applications for cancer. The invention finds use in the prevention, treatment, detection or research into any cancer, including prostrate, pancreas, colon, brain, lung, breast, bone, skin cancers. For example, the invention finds use in the prevention, treatment, detection of or research into endocrine system cancers, such as cancers of the thyroid, pituitary, and adrenal glands and the pancreatic islets; gastrointestinal cancers, such as cancer of the anus, colon, esophagus, gallbladder, stomach, liver, and rectum; genitourinary cancers such as cancer of the penis, prostate and testes; gynecological cancers, such as cancer of the ovaries, cervix, endometrium, uterus, fallopian tubes, vagina, and vulva; head and neck cancers, such as hypopharyngeal, laryngeal, oropharyngeal cancers, lip, mouth and oral cancers, cancer of the salivary gland, cancer of the digestive tract and sinus cancer; leukemia; lymphomas including Hodgkin's and non-Hodgkin's lymphoma; metastatic cancer; myelomas; sarcomas; skin cancer; urinary tract cancers including bladder, kidney and urethral cancers; and pediatric cancers, such as pediatric brain tumors, leukemia, lymphomas, sarcomas, liver cancer and neuroblastoma and retinoblastoma.

Before the present invention is described, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications and patent applications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

It must be noted that as used herein and in the appended claims, the singular forms “a”, “and”, and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a polynucleotide” includes a plurality of such polynucleotides and reference to “the cancer cell” includes reference to one or more cells and equivalents thereof known to those skilled in the art, and so forth.

The publications and applications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

Definitions

The terms “polynucleotide” and “nucleic acid”, used interchangeably herein, refer to polymeric forms of nucleotides of any length, either ribonucleotides or deoxynucleotides. Thus, these terms include, but are not limited to, single-, double-, or multi-stranded DNA or RNA, genomic DNA, cDNA, DNA-RNA hybrids, or a polymer comprising purine and pyrimidine bases or other natural, chemically or biochemically modified, non-natural, or derivatized nucleotide bases. These terms further include, but are not limited to, mRNA or cDNA that comprise intronic sequences (see, e.g., Niwa et al. (1999) Cell 99(7):691-702). The backbone of the polynucleotide can comprise sugars and phosphate groups (as may typically be found in RNA or DNA), or modified or substituted sugar or phosphate groups. Alternatively, the backbone of the polynucleotide can comprise a polymer of synthetic subunits such as phosphoramidites and thus can be an oligodeoxynucleoside phosphoramidate or a mixed phosphoramidate-phosphodiester oligomer. Peyrottes et al. (1996) Nucl. Acids Res. 24:1841-1848; Chaturvedi et al. (1996) Nucl. Acids Res. 24:2318-2323. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs, uracyl, other sugars, and linking groups such as fluororibose and thioate, and nucleotide branches. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component. Other types of modifications included in this definition are caps, substitution of one or more of the naturally occurring nucleotides with an analog, and introduction of means for attaching the polynucleotide to proteins, metal ions, labeling components, other polynucleotides, or a solid support. The term “polynucleotide” also encompasses peptidic nucleic acids (Pooga et al Curr Cancer Drug Targets. (2001) 1:231 -9).

A “gene product” is a biopolymeric product that is -expressed or produced by a gene. A gene product may be, for example, an unspliced RNA, an mRNA, a splice variant mRNA, a polypeptide, a post-translationally modified polypeptide, a splice variant polypeptide etc. Also encompassed by this term is biopolymeric products that are made using an RNA gene product as a template (i.e. cDNA of the RNA). A gene product may be made enzymatically, recombinantly, chemically, or within a cell to which the gene is native. In many embodiments, if the gene product is proteinaceous, it exhibits a biological activity. In many embodiments, if the gene product is a nucleic acid, it can be translated into a proteinaceous gene product that exhibits a biological activity.

A composition (e.g. a polynucleotide, polypeptide, antibody, or host cell) that is “isolated” or “in substantially isolated form” refers to a composition that is in an environment different from that in which the composition naturally occurs. For example, a polynucleotide that is in substantially isolated form is outside of the host cell in which the polynucleotide naturally occurs, and could be a purified fragment of DNA, could be part of a heterologous vector, or could be contained within a host cell that is not a host cell from which the polynucleotide naturally occurs. The term “isolatedA” does not refer to a genomic or cDNA library, whole cell total protein or mRNA preparation, genomic DNA preparation, or an isolated human chromosome. A composition which is in substantially isolated form is usually substantially purified.

As used herein, the term “substantially purified” refers to a compound (e.g., a polynucleotide, a polypeptide or an antibody, etc.,) that is removed from its natural environment and is usually at least 60% free, preferably 75% free, and most preferably 90% free from other components with which it is naturally associated. Thus, for example, a composition containing A is “substantially free of” B when at least 85% by weight of the total A+B in the composition is A. Preferably, A comprises at least about 90% by weight of the total of A+B in the composition, more preferably at least about 95% or even 99% by weight. In the case of polynucleotides, “A” and “B” may be two different genes positioned on different chromosomes or adjacently on the same chromosome, or two isolated cDNA species, for example.

The terms “polypeptide” and “protein”, interchangeably used herein, refer to a polymeric form of amino acids of any length, which can include coded and non-coded amino acids, chemically or biochemically modified or derivatized amino acids, and polypeptides having modified peptide backbones. The term includes fusion proteins, including, but not limited to, fusion proteins with a heterologous amino acid sequence, fusions with heterologous and homologous leader sequences, with or without N-terminal methionine residues; immunologically tagged proteins; and the like.

“Heterologous” refers to materials that are derived from different sources (e.g., from different genes, different species, etc.).

As used herein, the terms “a gene that is differentially expressed in a cancer cell,” and “a polynucleotide that is differentially expressed in a cancer cell” are used interchangeably herein, and generally refer to a polynucleotide that represents or corresponds to a gene that is differentially expressed in a cancerous cell when compared with a cell of the same cell type that is not cancerous, e.g., mRNA is found at levels at least about 25%, at least about 50% to about 75%, at least about 90%, at least about 1.5-fold, at least about 2-fold, at least about 5-fold, at least about 10-fold, or at least about 50-fold or more, different (e.g., higher or lower). The comparison can be made in tissue, for example, if one is using in situ hybridization or another assay method that allows some degree of discrimination among cell types in the tissue. The comparison may also or alternatively be made between cells removed from their tissue source.

“Differentially expressed polynucleotide” as used herein refers to a nucleic acid molecule (RNA or DNA) comprising a sequence that represents a differentially expressed gene, e.g., the differentially expressed polynucleotide comprises a sequence (e.g., an open reading frame encoding a gene product; a non-coding sequence) that uniquely identifies a differentially expressed gene so that detection of the differentially expressed polynucleotide in a sample is correlated with the presence of a differentially expressed gene in a sample. “Differentially expressed polynucleotidesz” is also meant to encompass fragments of the disclosed polynucleotides, e.g., fragments retaining biological activity, as well as nucleic acids homologous, substantially similar, or substantially identical (e.g., having about 90% sequence identity) to the disclosed polynucleotides.

“Corresponds to” or “represents” when used in the context of, for example, a polynucleotide or sequence that “corresponds to” or “represents” a gene means that at least a portion of a sequence of the polynucleotide is present in the gene or in the nucleic acid gene product (e.g., mRNA or cDNA). A subject nucleic acid may also be “identified” by a polynucleotide if the polynucleotide corresponds to or represents the gene. Genes identified by a polynucleotide may have all or a portion of the identifying sequence wholly present within an exon of a genomic sequence of the gene, or different portions of the sequence of the polynucleotide may be present in different exons (e.g., such that the contiguous polynucleotide sequence is present in an mRNA, either pre- or post-splicing, that is an expression product of the gene). In some embodiments, the polynucleotide may represent or correspond to a gene that is modified in a cancerous cell relative to a normal cell. The gene in the cancerous cell may contain a deletion, insertion, substitution, or translocation relative to the polynucleotide and may have altered regulatory sequences, or may encode a splice variant gene product, for example. The gene in the cancerous cell may be modified by insertion of an endogenous retrovirus, a transposable element, or other naturally occurring or non-naturally occurring nucleic acid. In most cases, a polynucleotide corresponds to or represents a gene if the sequence of the polynucleotide is most identical to the sequence of a gene or its product (e.g. mRNA or CDNA) as compared to other genes or their products. In most embodiments, the most identical gene is determined using a sequence comparison of a polynucleotide to a database of polynucleotides (e.g. GenBank) using the BLAST program at default settings For example, if the most similar gene in the human genome to an exemplary polynucleotide is the protein kinase C gene, the exemplary polynucleotide corresponds to protein kinase C. In most cases, the sequence of a fragment of an exemplary polynucleotide is at least 95%, 96%, 97%, 98%, 99% or up to 100% identical to a sequence of at least 15, 20, 25, 30, 35, 40, 45, or 50 contiguous nucleotides of a corresponding gene or its product (mRNA or cDNA), when nucleotides that are “N” represent G, A, T or C.

An “identifying sequence” is a minimal fragment of a sequence of contiguous nucleotides that uniquely identifies or defines a polynucleotide sequence or its complement. In many embodiments, a fragment of a polynucleotide uniquely identifies or defines a polynucleotide sequence or its complement. In some embodiments, the entire contiguous sequence of a gene, cDNA, EST, or other provided sequence is an identifying sequence.

“Diagnosis” as used herein generally includes determination of a subject's susceptibility to a disease or disorder, determination as to whether a subject is presently affected by a disease or disorder, prognosis of a subject affected by a disease or disorder (e.g., identification of pre-metastatic or metastatic cancerous states, stages of cancer, or responsiveness of cancer to therapy), and use of therametrics (e.g., monitoring a subject's condition to provide information as to the effect or efficacy of therapy).

As used herein, the term “a polypeptide associated with cancer” refers to a polypeptide encoded by a polynucleotide that is differentially expressed in a cancer cell.

The term “biological sample” encompasses a variety of sample types obtained from an organism and can be used in a diagnostic or monitoring assay. The term encompasses blood and other liquid samples of biological origin, solid tissue samples, such as a biopsy specimen or tissue cultures or-cells derived therefrom and the progeny thereof. The term encompasses samples that have been manipulated in any way after their procurement, such as by treatment with reagents, solubilization, or enrichment for certain components. The term encompasses a clinical sample, and also includes cells in cell culture, cell supernatants, cell lysates, serum, plasma, biological fluids, and tissue samples.

The terms “treatment”, “treating”, “treat” and the like are used herein to generally refer to obtaining a desired pharmacologic and/or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete stabilization or cure for a disease and/or adverse effect attributable to the disease. “Treatment” as used herein covers any treatment of a disease in a mammal, particularly a human, and includes: (a) preventing the disease or symptom from occurring in a subject which may be predisposed to the disease or symptom but has not yet been diagnosed as having it; (b) inhibiting the disease symptom, i.e., arresting its development; or (c) relieving the disease symptom, i.e., causing regression of the disease or symptom.

The terms “individual,” “subject,” “host,” and “patient,” used interchangeably herein and refer to any mammalian subject for whom diagnosis, treatment, or therapy is desired, particularly humans. Other subjects may include cattle, dogs, cats, guinea pigs, rabbits, rats, mice, horses, and the like.

A “host cell”, as used herein, refers to a microorganism or a eukaryotic cell or cell line cultured as a unicellular entity which can be, or has been, used as a recipient for a recombinant vector or other transfer polynucleotides, and include the progeny of the original cell which has been transfected. It is understood that the progeny of a single cell may not necessarily be completely identical in morphology or in genomic or total DNA complement as the original parent, due to natural, accidental,; or deliberate mutation.

The terms “cancer”, “neoplasm”, “tumor”, and “carcinoma”, are used interchangeably herein to refer to cells which exhibit relatively autonomous growth, so that they exhibit an aberrant growth phenotype characterized by a significant loss of control of cell proliferation. In general, cells of interest for detection or treatment in the present application include precancerous (e.g., benign), malignant, pre-metastatic, metastatic, and non-metastatic cells. Detection of cancerous cells is of particular interest.

The term “normal” as used in the context of “normal cell,” is meant to refer to a cell of an untransformed phenotype or exhibiting a morphology of a non-transformed cell of the tissue type being examined.

“Cancerous phenotype” generally refers to any of a variety of biological phenomena that are characteristic of a cancerous cell, which phenomena can vary with the type of cancer. The cancerous phenotype is generally identified by abnormalities in, for example, cell growth or proliferation (e.g., uncontrolled growth or proliferation), regulation of the cell cycle, cell mobility, cell-cell interaction, or metastasis, etc.

“Therapeutic target” generally refers to a gene or gene product that, upon modulation of its activity (e.g., by modulation of expression, biological activity, and the like), can provide for modulation of the cancerous phenotype.

As used throughout, “modulation” is meant to refer to an increase or a decrease in the indicated phenomenon (e.g., modulation of a biological activity refers to an increase in a biological activity or a decrease in a biological activity).

As used herein a “Group I type tumor” is a tumor comprising cells that, relative to a non-cancer cell of the same tissue type, exhibit increased expression of a gene product encoded by at least one or more of the following genes: IGF2, TTK, MAPKAPK2, MARCKS, BBS2, CETN2 CGI-148 protein, FGFR4, FHL3, FLJ22066, KIP2, MGC:29604, NQO2, and OGG1.

As used herein a “Group II type tumor” is a tumor comprising cells that, relative to a non-cancer cell of the same tissue type, exhibit increased expression of a gene product encoded by at least one or more of the following genes: IFITM (1-8U; 1-8D; 9-27), ITAK, and BIRC3/H-IAP 1.

As used herein a “Group I+II type tumor” is a tumor comprising cells that, relative to a non-cancer cell of the same tissue type, exhibit increased expression of 1) a gene product encoded by at least one or more of the following genes: IGF2, TTK, MAPKAPK2, MARCKS, BBS2, CETN2 CGI-148 protein, FGFR4, FHL3, FLJ22066, KIP2, MGC:29604, NQO2, and OGGI; and a gene product encoded by at least one or more of the following genes 2) IFITM (1-8U; 1-8D; 9-27), ITAK, and BIRC3/H-IAP1.

By “chondroitin 4-O sulfotransferase” is meant any polypeptide composition that exhibits chondroitin 4-O sulfotransferase activity. Examples of chondroitin 4-0 sulfotransferases include chondroitin 4-O sulfotransferase-1, -2, -3, defined by NCBI accession numbers AAF81691, AAF81692, and AAM5548 1, respectively. Assays for determining whether a polypeptide has chondroitin 4-O sulfotransferase activity are described in Burkart & Wong (Anal Biochem 274:131-137 (1999)), and further described below. Variants of chondroitin 4-O sulfotransferase include enzymes that retain chondroitin 4-O sulfotransferase activity, i.e. a sulfotransferase activity that is specific for chondroitin over other substrates. Variants of chondroitin 4-O sulfotransferase-1, -2, -3 that retain biological activity may be produced by substituting amino acids that are in equivalent positions between two chondroitin 4-O sulfotransferases, such as chondroitin 4-O sulfotransferase-1 and chondroitin 4-O sulfotransferase-2. A chondroitin 4-O sulfotransferase activity of interest is chondroitin 4-O sulfotransferase 2, (C4S-2).

By “chondroitin 4-O sulfotransferase 2” is meant a polypeptide that has chondroitin 4-O sulfotransferase activity and has significant sequence identity to the chondroitin 4-O sulfotransferase 2 of humans (NCBI accession number NP_(—)061111) or mouse (NCBI accession number NP_(—)067503). The alignment between these two polypeptides (mouse C4S-2 at the top and human C4S-2 at the bottom) is shown in FIG. 37 (from Hiraoaka at al-JBC 2000 275: 20188-96). Conserved sequences that are active sites, important for binding phosphate and phosphosulphate groups, are underlined in this figure. Variants of chondroitin 4-O sulfotransferase 2 that have chondroitin 4-O sulfotransferase 2 activity include the human and mice chondroitin 4-O sulfotransferase 2 polypeptides, and, for example, polypeptides that contain substitutions of amino acids at equivalent positions from e.g. the mouse to the human polypeptidies. Amino acids at positions 4, 16, 17, 28 and 29 are examples of such amino acids. Chondroitin 4-O sulfotransferase 2 has specificity for certain substrates with respect to other chondroitin 4-O sulfotransferases.

With regard to chondroitin 4-O sulfotransferases, further references of interest include Hiraoaka at al JBC 2000 275: 20188-96, Ricciardelli et al. Cancer Res. May 15, 1999; 59(10):2324-8, Ricciardelli et al. Clin Cancer Res. June 1997;3(6):983-92, Iida et al. Semin Cancer Biol. June 1996;7(3):155-62, Yamori et al. J Cell Biochem. April 1988; 36(4):405-16, Denholm et al. Eur J Pharmacol. Mar. 30, 2001; 416(3):213-21 and Bowman and Bertozzi Chem Biol. January 1999;6(1):R9-R22.

A “chondroitin 4-O sulfotransferase-related disorder” is a disorder that is associated with the abnormal expression (i.e. increased or decreased expression) of a chondroitin 4-O sulfotransferase or variant thereof. In certain embodiments, the “chondroitin 4-O sulfotransferase-related disorder” is a “chondroitin 4-O sulfotransferase-2-related disorder” associated with the abnormal expression of chondroitin 4-O sulfotransferase-2 or a variant thereof. These disorders are usually related to cancer, in particular cancers of the breast, colon, lung, brain, skin etc. In certain embodiments, the disorder relates to prostate cancer.

By “cyclin G associated kinase”, or “GAK” is meant any polypeptide composition that exhibits cyclin G associated kinase activity. Examples of cyclin G associated kinase include the polypeptide defined by NCBI accession number XM_(—)003450, NM_(—)005255, NP_(—)005246 and NM_(—)031030. Assays for determnimng whether a polypeptide has cyclin G associated kinase activity are described in Ausubel et al., eds., 1998, Current Protocols in Molecular Biology, John Wiley & Sons, NY. Variants of the human cyclin G associated kinase that retain biological activity may be produced by, inter alia, substituting amino acids that are in equivalent positions between two cyclin G associated kinases, such as the cyclin G associated kinases from rat and humans.

With regard to cyclin G associated kinases, further references of interest include: Kanaoka et al, FEBS Lett. Jan. 27, 1997;402(l):73-80; Kimura et al, Genomics. Sep. 1, 1997;44(2):179-87; Greener et al, J Biol Chem. Jan. 14, 2000;275(2):1365-70; and Korolchuk et al, Traffic. June 2002;3(6):428-39.

“DKFZP5661133” and “DKFZ” are used interchangeably herein to refer to a polypeptide composition that exhibits DKFZP5661133 activity. Assays for determining whether a polypeptide has DKFZP5661133 activity (i.e. for determining whether DKFZP5661133 may have intracytoplasmatic vacuole promoting activity) are described in Dusetti et al, (Biochem Biophys Res Commun. Jan. 18, 2002;290(2):641-9). Variants of the DKFZP5661133 that retain biological activity may be produced by, inter alia, substituting amino acids that are in equivalent positions between two DKFZP5661133, such as the DKFZp5661133 from rat and humans. DKFZ is also known as VMP1, or vacuole membrane protein 1.

Alternatively, “DKFZP566133”, or “DKFZ” refers to an amino acid sequence defined by NCBI accession number NP_(—)112200, AAH09758, NM_(—)138839, and NM_(—)030938, polynucleotides encoding the amino acid sequences set forth in these accession numbers (SEQ ID NO:3017and SEQ ID NO: 3018, respectively).

In addition, “DKFZP1133”, or “DKFZ” refers to the polynucleotide sequences represented by Spot ID NOS 22793, 26883 and 27450 (SEQ ID NOS: 2779-2780 and SEQ ID NOS: 2781-2782 and SEQ ID NOS: 2964-2965, respectively). FIG. 41 shows an alignment between Spot ID NOS: 22793, 26883 and VMP1 (NM_(—)030938) (i.e. DKFZ), identifying a VMP1 or DKFZ gene product as corresponding to these spot IDs. FIG. 42 depicts fragments of Spot ID NOS 22793, 26883, 27450 which align with VMP1 (SEQ ID NOS 3019, 3020, and 3021 respectively). These fragments, or their encoded products, may also be used as a DKFZ identifying sequence.

Ploynucleotide Compositions

The present invention provides isolated polynucleotides that contain nucleic acids that are differentially expressed in cancer cells. The polynucleotides, as well as any polypeptides encoded thereby, find use in a variety of therapeutic and diagnostic methods.

The scope of the invention with respect to compositions containing the isolated polynucleotides useful in the methods described herein includes, but is not necessarily limited to, polynucleotides having (i.e., comprising) a sequence set forth in any one of the polynucleotide sequences provided herein, or fragment thereof; polynucleotides obtained from the biological materials described herein or other biological sources (particularly human sources) by hybridization under stringent conditions (particularly conditions of high stringency); genes corresponding to the provided polynucleotides; cDNAs corresponding to the provided polynucleotides; variants of the provided polynucleotides and their corresponding genes, particularly those variants that retain a biological activity of the encoded gene product (e.g., a biological activity ascribed to a gene product corresponding to the provided polynucleotides as a result of the assignment of the gene product to a protein family(ies) and/or identification of a functional domain present in the gene product). Other nucleic acid compositions contemplated by and within the scope of the present invention will be readily apparent to one of ordinary skill in the art when provided with the disclosure here. “Polynucleotide” and “nucleic acid” as used herein with reference to nucleic acids of the composition is not intended to be limiting as to the length or structure of the nucleic acid unless specifically indicated.

The invention features polynucleotides that represent genes that are expressed in human tissue, specifically polynucleotides that are differentially expressed in tissues containing cancerous cells. Nucleic acid compositions described herein of particular interest are at least about 15 bp in length, at least about 30 bp in length, at least about 50 bp in length, at least about 100 bp, at least about 200 bp in length, at least about 300 bp in length, at least about 500 bp in length, at least about 800 bp in length, at least about 1 kb in length, at least about 2.0 kb in length, at least about 3.0 kb in length, at least about 5 kb in length, at least about 10 kb in length, at least about 50kb in length and are usually less than about 200 kb in length. These polynucleotides (or polynucleotide fragments) have uses that include, but are not limited to, diagnostic probes and primers as starting materials for probes and primers, as discussed herein.

The subject polynucleotides usually comprise a sequence set forth in any one of the polynucleotide sequences provided herein, for example, in the sequence listing, incorporated by reference in a table (e.g. by an NCBI accession number), a cDNA deposited at the A.T.C.C., or a fragment or variant thereof. A “fragment” or “portion” of a polynucleotide is a contiguous sequence of residues at least about 10 nt to about 12 nt, 15 nt, 16 nt, 18 nt or 20 nt in length, usually at least about 22 nt, 24 nt, 25 nt, 30 nt, 40 nt, 50 nt, 60nt, 70 nt, 80 nt, 90 nt, 100 nt to at least about 150 nt, 200 nt, 250 nt, 300 nt, 350 nt, 400 nt, 500 nt, 800 nt or up to about 1000 nt, 1500 or 2000 nt in length. In some embodiments, a fragment of a polynucleotide is the coding sequence of a polynucleotide. A fragment of a polynucleotide may start at position 1 (i.e. the first nucleotide) of a nucleotide sequence provided herein, or may start at about position 10, 20, 30, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1500 or 2000, or an ATG translational initiation codon of a nucleotide sequence provided herein. In this context “about” includes the particularly recited value or a value larger or smaller by several (5, 4, 3, 2, or 1) nucleotides. The described polynucleotides and fragments thereof find use as hybridization probes, PCR primers, BLAST probes, or as an identifying sequence, for example.

The subject nucleic acids may be variants or degenerate variants of a sequence provided herein. In general, a variants of a polynucleotide provided herein have a fragment of sequence identity that is greater than at least about 65%, greater than at least about 70%, greater than at least about 75%, greater than at least about 80%, greater than at least about 85%, or greater than at least about 90%, 95%, 96%, 97%, 98%, 99% or more (i.e. 100%) as compared to an identically sized fragment of a provided sequence. as determined by the Smith-Waterman homology search algorithm as implemented in MPSRCH program (Oxford Molecular). For the purposes of this invention, a preferred method of calculating percent identity is the Smith-Waterman algorithm. Global DNA sequence identity should be greater than 65% as determined by the Smith-Waterman homology search algorithm as implemented in MPSRCH program (Oxford Molecular) using an gap search with the following search parameters: gap open penalty, 12; and gap extension penalty, 1.

The subject nucleic acid compositions include full-length cDNAs or mRNAs that encompass an identifying sequence of contiguous nucleotides from any one of the polynucleotide sequences provided herein.

As discussed above, the polynucleotides useful in the methods described herein also include polynucleotide variants having sequence similarity or sequence identity. Nucleic acids having sequence similarity are detected by hybridization under low stringency conditions, for example, at 50° C. and 10×SSC (0.9 M saline/0.09 M sodium citrate) and remain bound when subjected to washing at 55° C. in 1×SSC. Sequence identity can be determined by hybridization under high stringency conditions, for example, at 50° C. or higher and 0.1×SSC (9 mM saline/0.9 mM sodium citrate). Hybridization methods and conditions are well known in the art, see, e.g., U.S. Pat. No. 5,707,829. Nucleic acids that are substantially identical to the provided polynucleotide sequences, e.g. allelic variants, genetically altered versions of the gene, etc., bind to the provided polynucleotide sequences under stringent hybridization conditions. By using probes, particularly labeled probes of DNA sequences, one can isolate homologous or related genes. The source of homologous genes can be any species, e.g. primate species, particularly human; rodents, such as rats and mice; canines, felines, bovines, ovines, equines, yeast, nematodes, etc.

In one embodiment, hybridization is performed using a fragment of at least 15 contiguous nucleotides (nt) of at least one of the polynucleotide sequences provided herein. That is, when at least 15 contiguous nt of one of the disclosed polynucleotide sequences is used as a probe, the probe will preferentially hybridize with a nucleic acid comprising the complementary sequence, allowing the identification and retrieval of the nucleic acids that uniquely hybridize to the selected probe. Probes from more than one polynucleotide sequence provided herein can hybridize with the same nucleic acid if the cDNA from which they were derived corresponds to one mRNA.

Polynucleotides contemplated for use in the invention also include those having a sequence of naturally occurring variants of the nucleotide sequences (e.g., degenerate variants (e.g., sequences that encode the same polypeptides but, due to the degenerate nature of the genetic code, different in nucleotide sequence), allelic variants, etc.). Variants of the polynucleotides contemplated by the invention are identified by hybridization of putative variants with nucleotide sequences disclosed herein, preferably by hybridization under stringent conditions. For example, by using appropriate wash conditions, variants of the polynucleotides described herein can be identified where the allelic variant exhibits at most about 25-30% base pair (bp) mismatches relative to the selected polynucleotide probe. In general, allelic variants contain 15-25% bp mismatches, and can contain as little as even 5-15%, or 2-5%, or 1-2% bp mismatches, as well as a single bp mismatch.

The invention also encompasses homologs corresponding to any one of the polynucleotide sequences provided herein, where the source of homologous genes can be any mammalian species, e.g., primate species, particularly human; rodents, such as rats; canines, felines, bovines, ovines, equines, yeast, nematodes, etc. Between mammalian species, e.g., human and mouse, homologs generally have substantial sequence similarity, e.g., at least 75% sequence identity, usually at least 80%%, at least 85, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or even 100% identity between nucleotide sequences. Sequence similarity is calculated based on a reference sequence, which may be a subset of a larger sequence, such as a conserved motif, coding region, flanking region, etc. A reference sequence will usually be at least about a fragment of a polynucleotide sequence and may extend to the complete sequence that is being compared. Algorithms for sequence analysis are known in the art, such as gapped BLAST, described in Altschul, et al. Nucleic Acids Res. (1997) 25:3389-3402, or TeraBLAST available from TimeLogic Corp. (Crystal Bay, Nev.).

The subject nucleic acids can be cDNAs or genomic DNAs, as well as fragments thereof, particularly fragments that encode a biologically active gene product and/or are useful in the methods disclosed herein (e.g., in diagnosis, as a unique identifier of a differentially expressed gene of interest, etc.). The term “cDNA” as used herein is intended to include all nucleic acids that share the arrangement of sequence elements found in native mature mRNA species, where sequence elements are exons and 3′ and 5′ non-coding regions. Normally mRNA species have contiguous exons, with the intervening introns, when present, being removed by nuclear RNA splicing, to create a continuous open reading frame encoding a polypeptide. mRNA species can also exist with both exons and introns, where the introns may be removed by alternative splicing. Furthermore it should be noted that different species of mRNAs encoded by the same genomic sequence can exist at varying levels in a cell, and detection of these various levels of mRNA species can be indicative of differential expression of the encoded gene product in the cell.

A genomic sequence of interest comprises the nucleic acid present between the initiation codon and the stop codon, as defined in the listed sequences, including all of the introns that are normally present in a native chromosome. It can further include the 3′ and 5′ untranslated regions found in the mature mRNA. It can further include specific transcriptional and translational regulatory sequences, such as promoters, enhancers, etc., including about 1 kb, but possibly more, of flanking genomic DNA at either the 5′ and 3′ end of the transcribed region. The genomic DNA can be isolated as a fragment of 100 kbp or smaller; and substantially free of flanking chromosomal sequence. The genomic DNA flanking the coding region, either 3′ and 5′, or internal regulatory sequences as sometimes found in introns, contains sequences required for proper tissue, stage-specific, or disease-state specific expression.

The nucleic acid compositions of the subject invention can encode all or a part of the naturally-occurring polypeptides. Double or single stranded fragments can be obtained from the DNA sequence by chemically synthesizing oligonucleotides in accordance with conventional methods, by restriction enzyme digestion, by PCR amplification, etc.

Probes specific to the polynucleotides described herein can be generated using the polynucleotide sequences disclosed herein. The probes are usually a fragment of a polynucleotide sequences provided herein. The probes can be synthesized chemically or can be generated from longer polynucleotides using restriction enzymes. The probes can be labeled, for example, with a radioactive, biotinylated, or fluorescent tag. Preferably, probes are designed based upon an identifying sequence of any one of the polynucleotide sequences provided herein. More preferably, probes are designed based on a contiguous sequence of one of the subject polynucleotides that remain unmasked following application of a masking program for masking low complexity (e.g., XBLAST, RepeatMasker, etc.) to the sequence., i.e., one would select an unmasked region, as indicated by the polynucleotides outside the poly-n stretches of the masked sequence produced by the masking program.

The polynucleotides of interest in the subject invention are isolated and obtained in substantial purity, generally as other than an intact chromosome. Usually, the polynucleotides, either as DNA or RNA, will be obtained substantially free of other naturally-occurring nucleic acid sequences that they are usually associated with, generally being at least about 50%, usually at least about 90% pure and are typically “recombinant”, e.g., flanked by one or more nucleotides with which it is not normally associated on a naturally occurring chromosome.

The polynucleotides described herein can be provided as a linear molecule or within a circular molecule, and can be provided within autonomously replicating molecules (vectors) or within molecules without replication sequences. Expression of the polynucleotides can be regulated by their own or by other regulatory sequences known in the art. The polynucleotides can be introduced into suitable host cells using a variety of techniques available in the art, such as transferrin polycation-mediated DNA transfer, transfection with naked or encapsulated nucleic acids, liposome-mediated DNA transfer, intracellular transportation of DNA-coated latex beads, protoplast fusion, viral infection, electroporation, gene gun, calcium phosphate-mediated transfection, and the like.

The nucleic acid compositions described herein can be used to, for example, produce polypeptides, as probes for the detection of mRNA in biological samples (e.g., extracts of human cells) or cDNA produced from such samples, to generate additional copies of the polynucleotides, to generate ribozymes or antisense oligonucleotides, and as single stranded DNA probes or as triple-strand forming oligonucleotides. The probes described herein can be used to, for example, determine the presence or absence of any one of the polynucleotide provided herein or variants thereof in a sample. These and other uses are described in more detail below.

Ploypeptides and Variants Thereof

The present invention further provides polypeptides encoded by polynucleotides that represent genes that are differentially expressed in cancer cells. Such polypeptides are referred to herein as “polypeptides associated with cancer.” The polypeptides can be used to generate antibodies specific for a polypeptide associated with cancer, which antibodies are in turn useful in diagnostic methods, prognostics methods, therametric methods, and the like as discussed in more detail herein. Polypeptides are also useful as targets for therapeutic intervention, as discussed in more detail herein.

The polypeptides contemplated by the invention include those encoded by the disclosed polynucleotides and the genes to which these polynucleotides correspond, as well as nucleic acids that, by virtue of the degeneracy of the genetic code, are not identical in sequence to the disclosed polynucleotides. Further polypeptides contemplated by the invention include polypeptides that are encoded by polynucleotides that hybridize to polynucleotide of the sequence listing. Thus, the invention includes within its scope-a polypeptide encoded by a polynucleotide having the sequence of any one of the polynucleotide sequences provided herein, or a variant thereof.

In general, the term “polypeptide” as used herein refers to both the full length polypeptide encoded by the recited polynucleotide, the polypeptide encoded by the gene represented by the recited polynucleotide, as well as portions or fragments thereof. “Polypeptides” also includes variants of the naturally occurring proteins, where such variants are homologous or substantially similar to the naturally occurring protein, and can be of an origin of the same or different species as the naturally occurring protein (e.g., human, murine, or some other species that naturally expresses the recited polypeptide, usually a mammalian species). In general, variant polypeptides have a sequence that has at least about 80%, usually at least about 90%, and more usually at least about 98% sequence identity with a differentially expressed polypeptide described herein, as measured by BLAST 2.0 using the parameters described above. The variant polypeptides can be naturally or non-naturally glycosylated, i.e., the polypeptide has a glycosylation pattern that differs from the glycosylation pattern found in the corresponding naturally occurring protein.

The invention also encompasses homologs of the disclosed polypeptides (or fragments thereof) where the homologs are isolated from other species, i.e. other animal or plant species, where such homologs, usually mammalian species, e.g. rodents, such as mice, rats; domestic animals, e.g., horse, cow, dog, cat; and humans. By “homolog” is meant a polypeptide having at least about 35%, usually at least about 40% and more usually at least about 60% amino acid sequence identity to a particular differentially expressed protein as identified above, where sequence identity is determined using the BLAST 2.0 algorithm, with the parameters described supra.

In general, the polypeptides of interest in the subject invention are provided in a non-naturally occurring environment, e.g. are separated from their naturally occurring environment. In certain embodiments, the subject protein is present in a composition that is enriched for the protein as compared to a cell or extract of a cell that naturally produces the protein. As such, isolated polypeptide is provided, where by “isolated” or “in substantially isolated form” is meant that the protein is present in a composition that is substantially free of other polypeptides, where by substantially free is meant that less than 90%, usually less than 60% and more usually less than 50% of the composition is made up of other polypeptides of a cell that the protein is naturally found.

Also within the scope of the invention are variants; variants of polypeptides include mutants, fragments, and fusions. Mutants can include amino acid substitutions, additions or deletions. The amino acid substitutions can be conservative amino acid substitutions or substitutions to eliminate non-essential amino acids, such as to alter a glycosylation site, a phosphorylation site or an acetylation site, or to minimize misfolding by substitution or deletion of one or more cysteine residues that are not necessary for function. Conservative amino acid substitutions are those that preserve the general charge, hydrophobicity/hydrophilicity, and/or steric bulk of the amino acid substituted.

Variants can be designed so as to retain or have enhanced biological activity of a particular region of the protein (e.g., a functional domain and/or, where the polypeptide is a member of a protein family, a region associated with a consensus sequence). For example, muteins can be made which are optimized for increased antigenicity, i.e. amino acid variants of a polypeptide may be made that increase the antigenicity of the polypeptide. Selection of amino acid alterations for production of variants can be based upon the accessibility (interior vs. exterior) of the amino acid (see, e.g., Go et al, Int. J Peptide Protein Res. (1980) 15:211), the thermnostability of the variant polypeptide (see, e.g., Querol et al., Prot. Eng. (1996) 9:265), desired glycosylation sites (see, e.g., Olsen and Thomsen, J. Gen. Microbiol. (1991) 137:579), desired disulfide bridges (see, e.g., Clarke et al., Biochemistry (1993) 32:4322; and Wakarchuk et al., Protein Eng. (1994) 7:1379), desired metal binding sites (see, e.g., Toma et al., Biochemistry (1991) 30:97, and Haezerbrouclk et al., Protein Eng. (1993) 6:643), and desired substitutions with in proline loops (see, e.g., Masul et al., Appl. Env. Microbiol. (1994) 60:3579). Cysteine-depleted muteins can be produced as disclosed in U.S. Pat. No. 4,959,314.Variants also include fragments of the polypeptides disclosed herein, particularly biologically active fragments and/or fragments corresponding to functional domains. Fragments of interest will typically be at least about 10 aa to at least about 15 aa in length, usually at least about 50 aa in length, and can be as long as 300 aa in length or longer, but will usually not exceed about 1000 aa in length, where the fragment will have a stretch of amino acids that is identical to a polypeptide encoded by a polynucleotide having a sequence of any one of the polynucleotide sequences provided herein, or a homolog thereof. The protein variants described herein are encoded by polynucleotides that are within the scope of the invention. The genetic code can be used to select the appropriate codons to construct the corresponding variants.

A fragment of a subject polypeptide is, for example, a polypeptide having an amino acid sequence which is a portion of a subject polypeptide e.g. a polypeptide encoded by a subject polynucleotide that is identified by any one of the sequence of SEQ ID NOS: 1-13996 or its complement. The polypeptide fragments of the invention are preferably at least about 9 aa, at least about 15 aa, and more preferably at least about 20 aa, still more preferably at least about 30 aa, and even more preferably, at least about 40 aa, at least about 50 aa, at least about 75 aa, at least about 100 aa, at least about 125 aa or at least about 150 aa in length. A fragment “at least 20 aa in length,” for example, is intended to include 20 or more contiguous amino acids from, for example, the polypeptide encoded by a cDNA, in a cDNA clone contained in a deposited library, or a nucleotide sequence shown in SEQ ID NOS: 1-13996 or the complementary stand thereof. In this context “about” includes the particularly recited value or a value larger or smaller by several (5, 4, 3, 2, or 1) amino acids. These polypeptide fragments have uses that include, but are not limited to, production of antibodies as discussed herein. Of course, larger fragments (e.g., at least 150, 175, 200, 250, 500, 600, 1000, or 2000 amino acids in length) are also encompassed by the invention.

Moreover, representative examples of polypeptides fragments of the invention (useful in, for example, as antigens for antibody production), include, for example, fragments comprising, or alternatively consisting of, a sequence from about amino acid number 1-10, 5-10, 10-20, 21-31, 31-40, 41-61, 61-81, 91-120, 121-140, 141-162, 162-200, 201-240, 241-280, 281- 320, 321-360, 360-400, 400-450, 451-500, 500-600, 600-700, 700-800, 800-900 and the like. In this context “about” includes the particularly recited range or a range larger or smaller by several (5, 4, 3, 2, or 1) amino acids, at either terminus or at both termini. In some embodiments, these fragments has a functional activity (e.g., biological activity) whereas in other embodiments, these fragments may be used to make an antibody.

In one example, a polynucleotide having a sequence set forth in the sequence listing, containing no flanking sequences (i.e., consisting of the sequence set forth in the sequence listing), may be cloned into an expression vector having ATG and a stop codon (e.g. any one of the pET vector from Invitrogen, or other similar vectors from other manufactures), and used to express a polypeptide of interest encoded by the polynucleotide in a suitable cell, e.g., a bacterial cell. Accordingly, the polynucleotides may be used to produce polypeptides, and these polypeptides may be used to produce antibodies by known methods described above and below. In many embodiments, the sequence of the encoded polypeptide does not have to be known prior to its expression in a cell. However, if it desirable to know the sequence of the polypeptide, this may be derived from the sequence of the polynucleotide. Using the genetic code, the polynucleotide may be translated by hand, or by computer means. Suitable software for identifying open reading frames and translating them into polypeptide sequences are well know in the art, and include: LasergeneTM from DNAStar (Madison, Wis.), and Vector NTI TM from Informax (Frederick Md.), and the like.

Further polypeptide variants mnay are described in PCT publications WO/00-55173 WO/01-07611 and WO/02-16429

Vectors, Host Cells and Protein Production

The present invention also relates to vectors containing the polynucleotide of the present invention, host cells, and the production of polypeptides by recombinant techniques. The vector may be, for example, a phage, plasmid, viral, or retroviral vector. Retroviral vectors may be replication competent or replication defective. In the latter case, viral propagation generally will occur only in complementing host cells.

The polynucleotides of the invention may be joined to a vector containing a selectable marker for propagation in a host. Generally, a plasmid vector is introduced in a precipitate, such as a calcium phosphate precipitate, or in a complex with a charged lipid. If the vector is a virus, it may be packaged in vitro using an appropriate packaging cell line and then transduced into host cells.

The polynucleotide insert should be operatively linked to an appropriate promoter, such as the phage lambda PL promoter, the E. coli lac, trp, phoA and tac promoters, the SV40 early and late promoters and promoters of retroviral LTRs, to name a few. Other suitable promoters will be known to the skilled artisan. The expression constructs will further contain sites for transcription initiation, termination, and, in the transcribed region, a ribosome binding site for translation. The coding portion of the transcripts expressed by the constructs will preferably include a translation initiating codon at the beginning and a termination codon (UAA, UGA or UAG) appropriately positioned at the end of the polypeptide to be translated.

As indicated, the expression vectors will preferably include at least one selectable marker. Such markers include dihydrofolate reductase, G418 or neomycin resistance for eukaryotic cell culture and tetracycline, kanamycin or ampicillin resistance genes for culturing in E. coli and other bacteria.

Representative examples of appropriate hosts include,but are not limited to, bacterial cells, such as E. coli, Streptomyces and Salmonella typhimurium cells; fungal cells, such as yeast cells (e.g., Saccharomyces cerevisiae or Pichia pastoris (ATCC Accession No. 201178)); insect cells such as Drosophila S2 and Spodoptera Sf9 cells; animal cells such as CHO, COS, 293, and Bowes melanoma cells; and plant cells. Appropriate-culture mediums and conditions for the above-described host cells are known in the art.

Among vectors preferred for use in bacteria include pQE70, pQE60 and pQE-9, available from QIAGEN, Inc.; pBluescript vectors, Phagescript vectors, pNHSA, pNH 16a, pNH 18A, pNH46A, available from Stratagene Cloning Systems, Inc.; and ptrc99a, pKK223-3, pKK233-3, pDR540, pRITS available from Pharmacia Biotech, Inc. Among preferred eukaryotic vectors are pWLNEO, pSV2CAT, pOG44, pXTI and pSG available from Stratagene; and pSVK3, pBPV, pMSG and pSVL available from Pharmacia. Preferred expression vectors for use in yeast systems include, but are not limited to pYES2, pYDI, pTEFl/Zeo, pYES2/GS, pPICZ, pGAPZ, pGAPZalph, pPIC9, pPIC3.5, pHIL-D2, pHIL-SI, pPIC3.5K, pPIC9K, and PA0815 (all available from Invitrogen, Carload, Calif.). Other suitable vectors will be readily apparent to the skilled artisan.

Nucleic acids of interest may be cloned into a suitable vector by route methods. Suitable vectors include plasmids, cosmids, recombinant viral vectors e.g. retroviral vectors, YACs, BACs and the like, phage vectors.

Introduction of the construct into the host cell can be effected by calcium phosphate transfection, DEAE-dextran mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection, or other methods. Such methods are described in many standard laboratory manuals, such as Davis et al., Basic Methods In Molecular Biology (1986). It is specifically contemplated that the polypeptides of the present invention may in fact be expressed by a host cell lacking a recombinant vector.

A polypeptide of this invention can be recovered and purified from recombinant cell cultures by well-known methods including ammonium-sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography and lectin chromatography. Most preferably, high performance liquid chromatography (“HPLC”) is employed for purification.

Polypeptides of the present invention can also be recovered from: products purified from natural sources, including bodily fluids, tissues and cells, whether directly isolated or cultured; products of chemical synthetic procedures; and products produced by recombinant techniques from a prokaryotic or eukaryotic host, including, for example, bacterial, yeast higher plant, insect, and mammalian cells. Depending upon the host employed in a recombinant production procedure, the polypeptides of the present invention may be glycosylated or may be non-glycosylated. In addition, polypeptides of the invention may also include an initial modified methionine residue, in some cases as a result of host mediated processes. Thus, it is well known in the art that the N-terminal methionine encoded by the translation initiation codon generally is removed with high efficiency from any protein after translation in all eukaryotic cells. While the N-terminal methionine on most proteins also is efficiently removed in most prokaryotes, for some proteins, this prokaryotic removal process is inefficient, depending on the nature of the amino acid to which the N-terminal methionine is covalently linked.

Suitable methods and compositions for polypeptide expression may be found in PCT publications WO/00-55173, WO/01-07611 and WO/02-16429, and suitable methods and compositions for production of modified polypeptides may be found in PCT publications WO/00-55173, WO/01-07611 and WO/02-16429.

Antibodies and Other Plypeptide or Polynucleotide Binding Molecule

The present invention further provides antibodies, which may be isolated antibodies, that are specific for a polypeptide encoded by a polynucleotide described herein and/or a polypeptide of a gene that corresponds to a polynucleotide described herein. Antibodies can be provided in a composition comprising the antibody and a buffer and/or a pharmaceutically acceptable excipient. Antibodies specific for a polypeptide associated with cancer are useful in a variety of diagnostic and therapeutic methods, as discussed in detail herein.

Gene products, including polypeptides, mRNA (particularly mRNAs having distinct secondary and/or tertiary structures), cDNA, or complete gene, can be prepared and used for raising antibodies for experimental, diagnostic, and therapeutic purposes. Antibodies may be used to identify a gene corresponding to a polynucleotide. The polynucleotide or related cDNA is expressed as described above, and antibodies are prepared. These antibodies are specific to an epitope on the polypeptide encoded by the polynucleotide, and can precipitate or bind to the corresponding native protein in a cell or tissue preparation or in a cell-free extract of an in vitro expression system.

Antibodies

Further polypeptides of the invention relate to antibodies and T-cell antigen receptors (TCR) which immunospecifically bind a subject polypeptide, subject polypeptide fragment, or variant thereof, and/or an epitope thereof (as determined by immunoassays well known in the art for assaying specific antibody-antigen binding). Antibodies of the invention include, but are not limited to, polyclonal, monoclonal, multispecific, human, humanized or chimeric antibodies, single chain antibodies, Fab fragments, F(ab′) fragments, fragments produced by a Fab expression library, anti-idiotypic (anti-Id) antibodies (including, e.g., anti-Id antibodies to antibodies of the invention), and epitope-binding fragments of any of the above. The term “antibody,” as used herein, refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen binding site that immunospecifically binds an antigen. The immunoglobulin molecules of the invention can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgGl, IgG2, lgG3, IgG4, IgAl and IgA2) or subclass of immunoglobulin molecule.

Most preferably the antibodies are human antigen-binding antibody fragments of the present invention and include, but are not limited to, Fab. Fab′ and F(ab′)2, Fd, single-chain Fvs (scFv), single-chain antibodies, disulfide-linked Fvs (sdFv) and fragments comprising either a VL or VH domain. Antigen-binding antibody fragments, including single-chain antibodies, may comprise the variable region(s) alone or in combination with the entirety or a portion of the following: hinge region, C_(H)1, C_(H)2, and C_(H)3 domains. Also included in the invention are antigen-binding fragments also comprising any combination of variable region(s) with a hinge region, C_(H)1, C_(H)2, and C_(H)3 domains. The antibodies of the invention may be from any animal origin including birds and mammals. Preferably, the antibodies are human, murine (e.g., mouse and rat), donkey, ship rabbit, goat, guinea pig, camel, horse, or chicken. As used herein, “human” antibodies include antibodies having the amino acid sequence of a human immunoglobulin and include antibodies isolated from, human immunoglobulin libraries or from animals transgenic for one or more human immunoglobulin and that do not express endogenous immunoglobulins, as described infra and, for example in, U.S. Pat. No. 5,939,598 by Kucherlapati et al.

The antibodies of the present invention may be monospecific, bispecific, trispecific or of greater multispecificity. Multispecific antibodies may be specific for different epitopes of a polypeptide of the present invention or may be specific for both a polypeptide of the present invention as well as for a heterologous epitope, such as a heterologous polypeptide or solid support material. See, e.g., PCT publications WO 93/17715; WO 92/08802; WO 91/00360; WO 92/05793; Tutt, et al., J. Immunol. 147:60-69 (199.1); U.S. Pat. Nos. 4,474,893; 4,714,681; 4,925,648; 5,573,920; 5,601,819; Kostelny et al., J. Immunol. 148:1547-1553 (1992).

Antibodies of the present invention may be described or specified in terms of the epitope(s) or portion(s) of a polypeptide of the present invention which they recognize or specifically bind. The epitope(s) or polypeptide portion(s) may be specified as described herein, e.g., by N-terminal and C-terminal positions, or by size in contiguous amino acid residues. Antibodies which specifically bind any epitope or polypeptide of the present invention may also be excluded. Therefore, the present invention includes antibodies that specifically bind polypeptides of the present invention, and allows for the exclusion of the same.

Antibodies of the present invention may also be described or specified in terms of their cross-reactivity. Antibodies that do not bind any other analog, ortholog, or homoiog of a polypeptide of the present invention are included. Antibodies that bind polypeptides with at least 95%, at least 90%, at least 85%, at least 80%, at least 75%, at least 70%, at least 65%, at least 60%, at least 55%, and at least 50% identity (as calculated using methods known in the art and described herein) to a polypeptide of the present invention are also included in the present invention. In specific embodiments, antibodies of the present invention cross-react with murine, rat and/or rabbit homologs of human proteins and the corresponding epitopes thereof Antibodies that do not bind polypeptides with less than 95%, less than 90%, less than 85%, less than 80%, less than 75%, less than 70%, less than 65%, less than 60%, less than 55%, and less than 50% identity (as calculated using methods known in the art and described herein) to a polypeptide of the present invention are also included in the present invention. In a specific embodiment, the above-described cross-reactivity is with respect to any single specific antigenic or immunogenic polypeptide, or combination(s) of 2, 3, 4, 5, or more of the specific antigenic and/or immunogenic polypeptides disclosed herein. Further included in the present invention are antibodies which bind polypeptides encoded by polynucleotides which hybridize to a polynucleotide of the present invention under stringent hybridization conditions (as described herein). Antibodies of the present invention may also be described or specified in terms of their binding affinity to a polypeptide of the invention. Preferred binding affinities include those with a dissociation constant or Kd less 5×10⁻⁵ M, 10⁻⁵ M, 5×10⁻⁶ M, 10⁻⁶ , 5×10⁻⁷ M, 10⁻⁷ M, 5×10⁻⁸ M, 10⁻⁸ M, 5×10 ⁻⁹ M, 10⁻⁹ M, 5×10−10 M, 10 -10 M, etc.

The invention also provides antibodies that competitively inhibit binding of an antibody to an epitope of the invention as determined by any method known in the art for determining competitive binding, for example, the immunoassays described herein. In preferred embodiments, the antibody competitively inhibits binding to the epitope by at least 95%, at least 90%, at least 85 %, at least 80%, at least 75%, at least 70%, at least 60%, or at least 50%.

Methods for making screening, assaying, humanizing, and modifying different types of antibody are well known in the art and may be found in PCT publications WO/00-55173, WO/01-07611 and WO/02-16429.

In addition, the invention further provides polynucleotides comprising a nucleotide sequence encoding an antibody of the invention and fragments thereof. The invention also encompasses polynucleotides that hybridize under stringent or alternatively, under lower stringency hybridization conditions, e.g., as defined supra, to polynucleotides that encode an antibody, preferably, that specifically binds to a polypeptide of the invention, preferably, an antibody that binds to a subject polypeptide.

The antibodies of the invention can be produced by any method known in the art for the synthesis of antibodies, in particular, by chemical synthesis or preferably, by recombinant expression techniques. Recombinant expression of an antibody of the invention, or fragment, derivative or analog thereof, (e.g., a heavy or light chain of an antibody of the invention or a single chain antibody of the invention), requires construction of an expression vector containing a polynucleotide that encodes the antibody. Once a polynucleotide encoding an antibody molecule or a heavy or light chain of an antibody, or portion thereof (preferably containing the heavy or light chain variable domain), of the invention has been obtained, the vector for the production of the antibody molecule may be produced by recombinant DNA technology using techniques well known in the art. Thus, methods for preparing a protein by expressing a polynucleotide containing an antibody encoding nucleotide sequence are described herein. Methods which are well known to those skilled in the art can be used to construct expression vectors containing antibody coding sequences and appropriate transcriptional and translational control signals. These methods include, for example, in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination. The invention, thus, provides replicable vectors comprising a nucleotide sequence encoding an antibody molecule of the invention, or a heavy or light chain thereof, or a heavy or light chain variable domain, operably linked to a promoter. Such vectors may include the nucleotide sequence encoding the constant region of the antibody molecule (see, e.g., PCT Publication WO 86/05807; PCT Publication WO 89/01036; and U.S. Pat. No. 5,122,464) and the variable domain of the antibody may be cloned into such a vector for expression of the entire heavy or light chain.

The expression vector is transferred to a host cell by conventional techniques and the transfected cells are then cultured by conventional techniques to produce an antibody of the invention. Thus, the invention includes host cells containing a polynucleotide encoding an antibody of the invention, or a heavy or light chain thereof, or a single chain antibody of the invention, operably linked to a heterologous promoter. In preferred embodiments for the expression of double-chained antibodies, vectors encoding both the heavy and light chains may be co-expressed in the host cell for expression of the entire immunoglobulin molecule, as detailed below.

A variety of host-expression vector systems may be utilized to express the antibody molecules of the invention. Such host-expression systems represent vehicles by which the coding sequences of interest may be produced and subsequently purified, but also represent cells which may, when transformed or transfected with the appropriate nucleotide coding sequences, express an antibody molecule of the invention in situ. These include but are not limited to microorganisms such as bacteria (e.g., E. coli, B. subtilis) transformed with recombinant bacteriophage DNA, plasmid DNA or cosmid DNA expression vectors containing antibody coding sequences; yeast (e.g., Saccharomyces, Pichia) transformed with recombinant yeast expression vectors containing antibody coding sequences; insect cell systems infected with recombinant virus expression vectors (e.g., baculovirus) containing antibody coding sequences; plant cell systems infected with recombinant virus expression vectors (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) or transformed with recombinant plasmid expression vectors (e.g., Ti plasmid) containing antibody coding sequences; or mammalian cell systems (e.g., COS, CHO, BHK, 293, 3T3 cells) harboring recombinant expression constructs containing promoters derived from the genome of mammalian cells (e.g., metallothionein promoter) or from mammalian viruses (e.g., the adenovirus late promoter; the vaccinia virus 7.5K promoter). Preferably, bacterial cells such as Escherichia coli, and more preferably, eukaryotic cells, especially for the expression of whole recombinant antibody molecule, are used for the expression of a recombinant antibody molecule. For example, mammalian cells such as Chinese hamster ovary cells (CHO), in conjunction with a vector such as the major intermediate early gene promoter element from human cytomegalovirus is an effective expression system for antibodies (Foecking et al., Gene 45:101 (1986); Cockett etal., Bio/Technology 8:2 (1990)).

Antibodies production is well known in the art. Exemplary methods and compositions for making antibodies may be found in PCT publications WO/00-55173, WO/01-07611 and WO/02-16429.

Immunophenotyping

The antibodies of the invention may be utilized for immunophenotyping of cell lines and biological samples. The translation product of the gene of the present invention may be useful as a cell specific marker, or more specifically as a cellular marker that is differentially expressed at various stages of differentiation and/or maturation of particular cell types. Monoclonal antibodies directed against a specific epitope, or combination of epitopes, will allow for the screening of cellular populations expressing the marker. Various techniques can be utilized using monoclonal antibodies to screen for cellular populations expressing the marker(s), and include magnetic separation using antibody-coated magnetic beads, “panning” with antibody attached to a solid matrix (i.e., plate), and flow cytometry (See, e.g., U.S. Pat. No. 5,985,660; and Morrison et al. Cell, 96:737-49 (1999)).

These techniques allow for the screening of particular populations of cells, such as might be found with hematological malignancies (i.e. minimal residual disease (MRD) in acute leukemic patients) and “non-self cells in transplantations to prevent Graft-versus-Host Disease (GVHD). Alternatively, these techniques allow for the screening of hematopoietic stem and progenitor cells capable of undergoing proliferation and/or differentiation, as might be found in human umbilical cord blood.

Kits

Also provided by the subject invention are kits for practicing the subject methods, as described above. The subject kits include at least one or more of: a subject nucleic acid, isolated polypeptide or an antibody thereto. Other optional components of the kit include: restriction enzymes, control primers and plasmids; buffers, cells, carriers adjuvents etc. The nucleic acids of the kit may also have restrictions sites, multiple cloning sites, primer sites, etc to facilitate their ligation other plasmids. The various components of the kit may be present in separate containers or certain compatible components may be precombined into a single container, as desired. In many embodiments, kits with unit doses of the active agent, e.g. in oral or injectable doses, are provided. In certain embodiments, controls, such as samples from a cancerous or non-cancerous cell are provided by the invention. Further embodiments of the kit include an antibody for a subject polypeptide and a chemotherapeutic agent to be used in combination with the polypeptide as a treatment.

In addition to above-mentioned components, the subject kits typically further include instructions for using the components of the kit to practice the subject methods. The instructions for practicing the subject methods are generally recorded on a suitable recording medium. For example, the instructions may be printed on a substrate, such as paper or plastic, etc. As such, the instructions may be present in the kits as a package insert, in the labeling of the container of the kit or components thereof (i.e., associated with the packaging or subpackaging) etc. In other embodiments, the instructions are present as an electronic storage data file present on a suitable computer readable storage medium, e.g. CD-ROM, diskette, etc. In yet other embodiments, the actual instructions are not present in the kit, but means for obtaining the instructions from a remote source, e.g. via the internet, are provided. An example of this embodiment is a kit that includes a web address where the instructions can be viewed and/or from which the instructions can be downloaded. As with the instructions, this means for obtaining the instructions is recorded on a suitable substrate.

Computer-Related Embodiments

In general, a library of polynucleotides is a collection of sequence information, which information is provided in either biochemical form (e.g., as a collection of polynucleotide molecules), or in electronic form (e.g., as a collection of polynucleotide sequences stored in a computer-readable form, as in a computer system and/or as part of a computer program). The sequence information of the polynucleotides can be used in a variety of ways, e.g., as a resource for gene discovery, as a representation of sequences expressed in a selected cell type (e.g., cell type markers), and/or as markers of a given disease or disease state. For example, in the instant case, the sequences of polynucleotides and polypeptides corresponding to genes differentially expressed in cancer, as well as the nucleic acid and amino acid sequences of the genes themselves, can be provided in electronic form in a computer database.

In general, a disease marker is a representation of a gene product that is present in all cells affected by disease either at an increased or decreased level relative to a normal cell (e.g., a cell of the same or similar type that is not substantially affected by disease). For example, a polynucleotide sequence in a library can be a polynucleotide that represents an mRNA, polypeptide, or other gene product encoded by the polynucleotide, that is either overexpressed or underexpressed in a cancerous cell affected by cancer relative to a normal (i.e., substantially disease-free) cell.

The nucleotide sequence information of the library can be embodied in any suitable form, e.g., electronic or biochemical forms. For example, a library of sequence information embodied in electronic form comprises an accessible computer data file (or, in biochemical form, a collection of nucleic acid molecules) that contains the representative nucleotide sequences of genes that are differentially expressed (e.g., overexpressed or underexpressed) as between, for example, i) a cancerous cell and a normal cell; ii) a cancerous cell and a dysplastic cell; iii) a cancerous cell and a cell affected by a disease or condition other than cancer; iv) a metastatic cancerous cell and a normal cell and/or non-metastatic cancerous cell; v) a malignant cancerous cell and a non-malignant cancerous cell (or a normal cell) and/or vi) a dysplastic cell relative to a normal cell. Other combinations and comparisons of cells affected by various diseases or stages of disease will be readily apparent to the ordinarily skilled artisan. Biochemical embodiments of the library include a collection of nucleic acids that have the sequences of the genes in the library, where the nucleic acids can correspond to the entire gene in the library or to a fragment thereof, as described in greater detail below.

The polynucleotide libraries of the subject invention generally comprise sequence information of a plurality of polynucleotide sequences, where at least one of the polynucleotides has a sequence of any of sequence described herein. By plurality is meant at least 2, usually at least 3 and can include up to all of the sequences described herein. The length and number of polynucleotides in the library will vary with the nature of the library, e.g., if the library is an oligonucleotide array, a cDNA array, a computer database of the sequence information, etc.

Where the library is an electronic library, the nucleic acid sequence information can be present in a variety of media. “Media” refers to a manufacture, other than an isolated nucleic acid molecule, that contains the sequence information of the present invention. Such a manufacture provides the genome sequence or a subset thereof in a form that can be examined by means not directly applicable to the sequence as it exists in a nucleic acid. For example, the nucleotide sequence of the present invention, e.g. the nucleic acid sequences of any of the polynucleotides of the sequences described herein, can be recorded on computer readable media, e.g. any medium that can be read and accessed directly by a computer. Such media include, but are not limited to: magnetic storage media, such as a floppy disc, a hard disc storage medium, and a magnetic tape; optical storage media such as CD-ROM; electrical storage media such as RAM and ROM; and hybrids of these categories such as magnetic/optical storage media.

One of skill in the art can readily appreciate how any of the presently known computer readable mediums can be used to create a manufacture comprising a recording of the present sequence information. “Recorded” refers to a process for storing information on computer readable medium, using any such methods as known in the art. Any convenient data storage structure can be chosen, based on the means used to access the stored information. A variety of data processor programs and formats can be used for storage, e.g. word processing text file, database format, etc. In addition to the sequence information, electronic versions of libraries comprising one or more sequence described herein can be provided in conjunction or connection with other computer-readable information and/or other types of computer-readable files (e.g., searchable files, executable files, etc, including, but not limited to, for example, search program software, etc.).

By providing the nucleotide sequence in computer readable form, the information can be accessed for a variety of purposes. Computer software to access sequence information (e.g. the NCBI sequence database) is publicly available. For example, the gapped BLAST (Altschul et al., Nucleic Acids Res. (1997) 25:3389-3402) and BLAZE (Brutlag et al, Comp. Chem. (1993) 17:203) search algorithms on a Sybase system, or the TeraBLAST (TimeLogic, Crystal Bay, Nev.) program optionally running on a specialized computer platform available from TimeLogic, can be used to identify open reading frames (ORFs) within the genome that contain homology to ORFs from other organisms.

As used herein, “a computer-based system” refers to the hardware means, software means, and data storage means used to analyze the nucleotide sequence information of the present invention. The minimum hardware of the computer-based systems of the present invention comprises a central processing unit (CPU), input means, output means, and data storage means. A skilled artisan can readily appreciate that any one of the currently available computer-based system are suitable for use in the present invention. The data storage means can comprise any manufacture comprising a recording of the present sequence information as described above, or a memory access means that can access such a manufacture.

“Search means” refers to one or more programs implemented on the computer-based system, to compare a target sequence or target structural motif, or expression levels of a polynucleotide in a sample, with the stored sequence information. Search means can be used to identify fragments or regions of the genome that match a particular target sequence or target motif. A variety of known algorithms are publicly known and commercially available, e.g. MacPattern (EMBL), TeraBLAST (TimeLogic), BLASTN and BLASTX (NCBI). A “target sequence” can be any polynucleotide or amino acid sequence of six or more contiguous nucleotides or two or more amino acids, preferably from about 10 to 100 amino acids or from about 30 to 300 nt. A variety of means for comparing nucleic acids or polypeptides may be used to compare accomplish a sequence comparison (e.g., to analyze target sequences, target motifs, or relative expression levels) with the data storage means. A skilled artisan can readily recognize that any one of the publicly available homology search programs can be used to search the computer based systems of the present invention to compare of target sequences and motifs. Computer programs to analyze expression levels in a sample and in controls are also known in the art.

A “target structural motif,” or “target motif,” refers to any rationally selected sequence or combination of sequences in which the sequence(s) are chosen based on a three-dimensional configuration that is formed upon the folding of the target motif, or on consensus sequences of regulatory or active sites. There are a variety of target motifs known in the art. Protein target motifs include, but are not limited to, enzyme active sites and signal sequences, kinase domains, receptor binding domains, SH2 domains, SH3 domains, phosphorylation sites, protein interaction domains, transmembrane domains, etc. Nucleic acid target motifs include, but are not limited to, hairpin structures, promoter sequences and other expression elements such as binding sites for transcription factors.

A variety of structural formats for the input and output means can be used to input and output the information in the computer-based systems of the present invention. One format for an output means ranks the relative expression levels of different polynucleotides. Such presentation provides a skilled artisan with a ranking of relative expression levels to determine a gene expression profile. A gene expression profile can be generated from, for example, a cDNA library prepared from mRNA isolated from a test cell suspected of being cancerous or pre-cancerous, comparing the sequences or partial sequences of the clones against the sequences in an electronic database, where the sequences of the electronic database represent genes differentially expressed in a cancerous cell, e.g., a cancerous breast cell. The number of clones having a sequence that has substantial similarity to a sequence that represents a gene differentially expressed in a cancerous cell is then determined, and the number of clones corresponding to each of such genes is determined. An increased number of clones that correspond to differentially expressed gene is present in the cDNA library of the test cell (relative to, for example, the number of clones expected in a cDNA of a normal cell) indicates that the test cell is cancerous.

As discussed above, the “library” as used herein also encompasses biochemical libraries of the polynucleotides of the sequences described herein, e.g., collections of nucleic acids representing the provided polynucleotides. The biochemical libraries can take a variety of forms, e.g., a solution of cDNAs, a pattern of probe nucleic acids stably associated with a surface of a solid support (i.e, an array) and the like. Of particular interest are nucleic acid arrays in which one or more of the genes described herein is represented by a sequence on the array. By array is meant an article of manufacture that has at least a substrate with at least two distinct nucleic acid targets on one of its surfaces, where the number of distinct nucleic acids can be considerably higher, typically being at least 10 nt, usually at least 20 nt and often at least 25 nt. A variety of different array formats have been developed and are known to those of skill in the art. The arrays of the subject invention find use in a variety of applications, including gene expression analysis, drug screening, mutation analysis and the like, as disclosed in the above-listed exemplary patent documents.

In addition to the above nucleic acid libraries, analogous libraries of polypeptides are also provided, where the polypeptides of the library will represent at least a portion of the polypeptides encoded by a gene corresponding to a sequence described herein.

Diagnostic and Other Methods Invloving Detection of Differentially Expressed Genes

The present invention provides methods of using the polynucleotides described herein in, for example, diagnosis of cancer and classification of cancer cells according to expression profiles. In specific non-limiting embodiments, the methods are useful for detecting cancer cells, facilitating diagnosis of cancer and the severity of a cancer (e.g., tumor grade, tumor burden, and the like) in a subject, facilitating a determination of the prognosis of a subject, and assessing the responsiveness of the subject to therapy (e.g., by providing a measure of therapeutic effect through, for example, assessing tumor burden during or following a chemotherapeutic regimen). Detection can be based on detection of a polynucleotide that is differentially expressed in a cancer cell, and/or detection of a polypeptide encoded by a polynucleotide that is differentially expressed in a cancer cell (“a polypeptide associated with cancer”). The detection methods of the invention can be conducted in vitro or in vivo, on isolated cells, or in whole tissues or a bodily fluid, e.g., blood, plasma, serum, urine, and the like).

In general, methods of the invention involving detection of a gene product (e.g., mRNA, cDNA generated from such mRNA, and polypeptides) involve contacting a sample with a probe specific for the gene product of interest. “Probe” as used herein in such methods is meant to refer to a molecule that specifically binds a gene product of interest (e.g., the probe binds to the target gene product with a specificity sufficient to distinguish binding to target over non-specific binding to non-target (background) molecules). “Probes” include, but are not necessarily limited to, nucleic acid probes (e.g., DNA, RNA, modified nucleic acid, and the like), antibodies (e.g., antibodies, antibody fragments that retain binding to a target epitope, single chain antibodies, and the like), or other polypeptide, peptide, or molecule (e.g., receptor ligand) that specifically binds a target gene product of interest.

The probe and sample suspected of having the gene product of interest are contacted under conditions suitable for binding of the probe to the gene product. For example, contacting is generally for a time sufficient to allow binding of the probe to the gene product (e.g., from several minutes to a few hours), and at a temperature and conditions of osmolarity and the like that provide for binding of the probe to the gene product at a level that is sufficiently distinguishable from background binding of the probe (e.g., under conditions that minimize non-specific binding). Suitable conditions for probe-target gene product binding can be readily determined using controls and other techniques available and known to one of ordinary skill in the art.

In this embodiment, the probe can be an antibody or other polypeptide, peptide, or molecule (e.g., receptor ligand) that specifically binds a target polypeptide of interest.

The detection methods can be provided as part of a kit. Thus, the invention further provides kits for detecting the presence and/or a level of a polynucleotide that is differentially expressed in a cancer cell (e.g., by detection of an mRNA encoded by the differentially expressed gene of interest), and/or a polypeptide encoded thereby, in a biological sample. Procedures using these kits can be performed by clinical laboratories, experimental laboratories, medical practitioners, or private individuals. The kits of the invention for detecting a polypeptide encoded by a polynucleotide that is differentially expressed in a cancer cell comprise a moiety that specifically binds the polypeptide, which may be a specific antibody. The kits of the invention for detecting a polynucleotide that is differentially expressed in a cancer cell comprise a moiety that specifically hybridizes to such a polynucleotide. The kit may optionally provide additional components that are useful in the procedure, including, but not limited to, buffers, developing reagents, labels, reacting surfaces, means for detection, control samples, standards, instructions, and interpretive information.

Detecting a Polypeptide Encoded by a Polynucleotide that is Differentially Expressed in a Cancer Cell

In some embodiments, methods are provided for a detecting cancer cell by detecting in a cell, a polypeptide encoded by a gene differentially expressed in a cancer cell. Any of a variety of known methods can be used for detection, including, but not limited to, immunoassay, using an antibody specific for the encoded polypeptide, e.g., by enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), and the like; and functional assays for the encoded polypeptide, e.g., binding activity or enzymatic activity.

For example, an immunofluorescence assay can be easily performed on cells without first isolating the encoded polypeptide. The cells are first fixed onto a solid support, such as a microscope slide or microtiter well. This fixing step can pen-neabilize the cell membrane. The permeablization of the cell membrane permits the polypeptide-specific probe (e.g, antibody) to bind. Alternatively, where the polypeptide is secreted or membrane-bound, or is otherwise accessible at the cell-surface (e.g., receptors, and other molecule stably-associated with the outer cell membrane or otherwise stably associated with the cell membrane, such permneabilization may not be necessary.

Next, the fixed cells are exposed to an antibody specific for the encoded polypeptide. To increase the sensitivity of the assay, the fixed cells may be further exposed to a second antibody, which is labeled and binds to the first antibody, which is specific for the encoded polypeptide. Typically, the secondary antibody is detectably labeled, e.g., with a fluorescent marker. The cells which express the encoded polypeptide will be fluorescently labeled and easily visualized under the microscope. See, for example, Hashido et al. (1992) Biochem. Biophys. Res. Comm. 187:1241-1248.

As will be readily apparent to the ordinarily skilled artisan upon reading the present specification, the detection methods and other methods described herein can be varied. Such variations are within the intended scope of the invention. For example, in the above detection scheme, the probe for use in detection can be immobilized on a solid support, and the test sample contacted with the immobilized probe. Binding of the test sample to the probe can then be detected in a variety of ways, e.g., by detecting a detectable label bound to the test sample.

The present invention further provides methods for detecting the presence of and/or measuring a level of a polypeptide in a biological sample, which polypeptide is encoded by a polynucleotide that represents a gene differentially expressed in cancer, particularly in a polynucleotide that represents a gene differentially cancer cell, using a probe specific for the encoded polypeptide. In this embodiment, the probe can be a an antibody or other polypeptide, peptide, or molecule (e.g., receptor ligand) that specifically binds a target polypeptide of interest.

The methods generally comprise: a) contacting the sample with an antibody specific for a differentially expressed polypeptide in a test cell; and b) detecting binding between the antibody and molecules of the sample. The level of antibody binding (either qualitative or quantitative) indicates the cancerous state of the cell. For example, where the differentially expressed gene is increased in cancerous cells, detection of an increased level of antibody binding to the test sample relative to antibody binding level associated with a normal cell indicates that the test cell is cancerous.

Suitable controls include a sample known not to contain the encoded polypeptide; and a sample contacted with an antibody not specific for the encoded polypeptide, e.g., an anti-idiotype antibody. A variety of methods to detect specific antibody-antigen interactions are known in the art and-can be used in the method, including, but not limited to, standard immunohistological methods, immunoprecipitation, an enzyme immunoassay, and a radioimmunoassay.

In general, the specific antibody will be detectably labeled, either directly or indirectly. Direct labels include radioisotopes; enzymes whose products are detectable (e.g., luciferase, β-galactosidase, and the like); fluorescent labels (e.g., fluorescein isothiocyanate, rhodamine, phycoerythrin, and the like); fluorescence emitting metals, e.g., 152Eu, or others of the lanthanide series, attached to the antibody through metal chelating groups such as EDTA; chemiluminescent compounds, e.g., luminol, isoluminol, acridinium salts, and the like; bioluminescent compounds, e.g., luciferin, aequorin (green fluorescent protein), and the like.

The antibody may be attached (coupled) to an insoluble support, such as a polystyrene plate or a bead. Indirect labels include second antibodies specific for antibodies specific for the encoded polypeptide (“first specific antibody”), wherein the second antibody is labeled as described above; and members of specific binding pairs, e.g., biotin-avidin, and the like. The biological sample may be brought into contact with and immobilized on a solid support or carrier, such as nitrocellulose, that is capable of immobilizing cells, cell particles, or soluble proteins. The support may then be washed with suitable buffers, followed by contacting with a detectably-labeled first specific antibody. Detection methods are known in the art and will be chosen as appropriate to the signal emitted by the detectable label. Detection is generally accomplished in comparison to suitable controls, and to appropriate standards.

In some embodiments, the methods are adapted for use in vivo, e.g., to locate or identify sites where cancer cells are present. In these embodiments, a detectably-labeled moiety, e.g., an antibody, which is specific for a cancer-associated polypeptide is administered to an individual (e.g., by injection), and labeled cells are located using standard imaging techniques, including, but not limited to, magnetic resonance imaging, computed tomography scanning, and the like. In this manner, cancer cells are differentially labeled.

Detecting a Polynucleotide that Represents a Gene Differentially Expressed in a Cancer Cell

In some embodiments, methods are provided for detecting a cancer cell by detecting expression in the cell of a transcript or that is differentially expressed in a cancer cell. Any of a variety of known methods can be used for detection, including, but not limited to, detection of a transcript by hybridization with a polynucleotide that hybridizes to a polynucleotide that is differentially expressed in a cancer cell; detection of a transcript by a polymerase chain reaction using specific oligonucleotide primers; in situ hybridization of a cell using as a probe a polynucleotide that hybridizes to a gene that is differentially expressed in a cancer cell and the like.

In many embodiments, the levels of a subject gene product are measured. By measured is meant qualitatively or quantitatively estimating the level of the gene product in a first biological sample either directly (e.g. by determining or estimating absolute levels of gene product) or relatively by comparing the levels to a second control biological sample. In many embodiments the second control biological sample is obtained from an individual not having not having cancer. As will be appreciated in the art, once a standard control level of gene expression is known, it can be used repeatedly as a standard for comparison. Other control samples include samples of cancerous tissue.

The methods can be used to detect and/or measure mRNA levels of a gene that is differentially expressed in a cancer cell. In some embodiments, the methods comprise: a) contacting a sample with a polynucleotide that corresponds to a differentially expressed gene described herein under conditions that allow hybridization; and b) detecting hybridization, if any. Detection of differential hybridization, when compared to a suitable control, is an indication of the presence in the sample of a polynucleotide that is differentially expressed in a cancer cell. Appropriate controls include, for example, a sample that is known not to contain a polynucleotide that is differentially expressed in a cancer cell. Conditions that allow hybridization are known in the art, and have been described in more detail above.

Detection can also be accomplished by any known method, including, but not limited to, in situ hybridization, PCR (polymerase chain reaction), RT-PCR (reverse transcription-PCR), and “Northern” or RNA blotting, arrays, microarrays, etc, or combinations of such techniques, using a suitably labeled polynucleotide. A variety of labels and labeling methods for polynucleotides are known in the art and can be used in the assay methods of the invention. Specific hybridization can be determined by comparison to appropriate controls.

Polynucleotides described herein are used for a variety of purposes, such as probes for detection of and/or measurement of, transcription levels of a polynucleotide that is differentially expressed in a cancer cell. Additional disclosure about preferred regions of the disclosed polynucleotide sequences is found in the Examples. A probe that hybridizes specifically to a polynucleotide disclosed herein should provide a detection signal at least 2-, 5-, 10-, or 20-fold higher than the background hybridization provided with other unrelated sequences. It should be noted that “probe” as used in this context of detection of nucleic acid is meant to refer to a polynucleotide sequence used to detect a differentially expressed gene product in a test sample. As will be readily appreciated by the ordinarily skilled artisan, the probe can be detectably labeled and contacted with, for example, an array comprising immobilized polynucleotides obtained from a test sample (e.g., mRNA). Alternatively, the probe can be immobilized on an array and the test sample detectably labeled. These and other variations of the methods of the invention are well within the skill in the art and are within the scope of the invention.

Labeled nucleic acid probes may be used to detect expression of a gene corresponding to the provided polynucleotide. In Northern blots, mRNA is separated electrophoretically and contacted with a probe. A probe is detected as hybridizing to an mRNA species of a particular size. The amount of hybridization can be quantitated to determine relative amounts of expression, for example under a particular condition. Probes are used for in situ hybridization to cells to detect expression. Probes can also be used in vivo for diagnostic detection of hybridizing sequences. Probes are typically labeled with a radioactive isotope. Other types of detectable labels can be used such as chromophores, fluorophores, and enzymes. Other examples of nucleotide hybridization assays are described in WO092/02526 and U.S. Pat. No. 5,124,246.

PCR is another means for detecting small amounts of target nucleic acids, methods for which may be found in Sambrook, et al. Molecular Cloning: A Laboratory Manual, CSH Press 1989, pp.14.2-14.33.

A detectable label may be included in the amplification reaction. Suitable detectable labels include fluorochromes,(e.g. fluorescein isothiocyanate (FITC), rhodamine, Texas Red, phycoerythrin, allophycocyanin, 6-carboxyfluorescein (6-FAM), 2′, 7′-dimethoxy-4′,5′-dichloro-6-carboxyfluorescein, 6-carboxy-X-rhodamine (ROX), 6-carboxy-2′,4′,7′,4,7-hexachlorofluorescein (HEX), 5-carboxyfluorescein (5-FAM) or N,N,N′,N′-tetramethyl-6-carboxyrhodamine (TAMRA)), radioactive labels, (e.g. ³²P, ³⁵s, ³H, etc.), and the like. The label may be a two stage system, where the polynucleotides is conjugated to biotin, haptens, etc. having a high affinity binding partner, e.g. avidin, specific antibodies, etc., where the binding partner is conjugated to a detectable label. The label may be conjugated to one or both of the primers. Alternatively, the pool of nucleotides used in the amplification is labeled, so as to incorporate the label into the amplification product.

Arrays

Polynucleotide arrays provide a high throughput technique that can assay a large number of polynucleotides or polypeptides in a sample. This technology can be used as a tool to test for differential expression.

A variety of methods of producing arrays, as well as variations of these methods, are known in the art and contemplated for use in the invention. For example, arrays can be created by spotting polynucleotide probes onto a substrate (e.g., glass, nitrocellulose, etc.) in a two-dimensional matrix or array having bound probes. The probes can be bound to the substrate by either covalent bonds or by non-specific interactions, such as hydrophobic interactions.

Samples of polynucleotides can be detectably labeled (e.g., using radioactive or fluorescent labels) and then hybridized to the probes. Double stranded polynucleotides, comprising the labeled sample polynucleotides bound to probe polynucleotides, can be detected once the unbound portion of the sample is washed away. Alternatively, the polynucleotides of the test sample can be immobilized on the array, and the probes detectably labeled. Techniques for constructing arrays and methods of using these arrays are described in, for example, Schena et al. (1996) Proc Natl Acad Sci USA. 93(20):10614-9; Schena et al. (1995) Science 270(5235):467-70; Shalon et al. (1996) Genome Res. 6(7):639-45, U.S. Pat. No. 5,807,522, EP 799 897; WO 97/29212; WO 97/27317; EP 785 280; WO 97/02357; U.S. Pat. No. 5,593,839; U.S. Pat. No. 5,578,832; EP 728 520; U.S. Pat. No. 5,599,695; EP 721.016; U.S. Pat. No. 5,556,752; WO 95/22058; and U.S. Pat. No. 5,631,734. In most embodiments, the “probe” is detectably labeled. In other embodiments, the probe is immobilized on the array and not detectably labeled.

Arrays can be used, for example, to examine differential expression of genes and can be used to determine gene function. For example, arrays can be used to detect differential expression of a gene corresponding to a polynucleotide described herein, where expression is compared between a test cell and control cell (e.g., cancer cells and normal cells). For example, high expression of a particular message in a cancer cell, which is not observed in a corresponding normal cell, can indicate a cancer specific gene product. Exemplary uses of arrays are further described in, for example, Pappalarado et al., Sem. Radiation Oncol. (1998) 8:217; and Ramsay, Nature Biotechnol. (1998) 16:40. Furthermore, many variations on methods of detection using arrays are well within the skill in the art and within the scope of the present invention. For example, rather than immobilizing the probe to a solid support, the test sample can be immobilized on a solid support which is then contacted with the probe.

Diagnosis, Prognosis, Assessment of Therapy (Theremetrics), and Management of Cancer

The-polynucleotides described herein, as well as their gene products and corresponding genes and gene products, are of particular interest as genetic or biochemical markers (e.g., in blood or tissues) that will detect the earliest changes along the carcinogenesis pathway and/or to monitor the efficacy of various therapies and preventive interventions.

For example, the level of expression of certain polynucleotides can be indicative of a poorer prognosis, and therefore warrant more aggressive chemo- or radio-therapy for a patient or vice versa. The correlation of novel surrogate tumor specific features with response to treatment and outcome in patients can define prognostic indicators that allow the design of tailored therapy based on the molecular profile of the tumor. These therapies include antibody targeting, antagonists (e.g., small molecules), and gene therapy.

Determining expression of certain polynucleotides and comparison of a patient's profile with known expression in normal tissue and variants of the disease allows a determination of the best possible treatment for a patient, both in terms of specificity of treatment and in terms of comfort level of the patient. Surrogate tumor markers, such as polynucleotide expression, can also be used to better classify, and thus diagnose and treat, different forms and disease states of cancer. Two classifications widely used in oncology that can benefit from identification of the expression levels of the genes corresponding to the polynucleotides described herein are staging of the cancerous disorder, and grading the nature of the cancerous tissue.

The polynucleotides that correspond to differentially expressed genes, as well as their encoded gene products, can be useful to monitor patients having or susceptible to cancer to detect potentially malignant events at a molecular level before they are detectable at a gross morphological level. In addition, the polynucleotides described herein, as well as the genes corresponding to such polynucleotides, can be useful as therametrics, e.g., to assess the effectiveness of therapy by using the polynucleotides or their encoded gene products, to assess, for example, tumor burden in the patient before, during, and after therapy.

Furthermore, a polynucleotide identified as corresponding to a gene that is differentially expressed in, and thus is important for, one type of cancer can also have implications for development or risk of development of other types of cancer, e.g., where a polynucleotide represents a gene differentially expressed across various cancer types. Thus, for example, expression of a polynucleotide corresponding to a gene that has clinical implications for cancer can also have clinical implications for metastatic breast cancer, colon cancer, or ovarian cancer, etc.

Staging. Staging is a process used by physicians to describe how advanced the cancerous state is in a patient. Staging assists the physician in determining a prognosis, planning treatment and evaluating the results of such treatment. Staging systems vary with the types of cancer, but generally involve the following “TNM” system: the type of tumor, indicated by T; whether the cancer has metastasized to nearby lymph nodes, indicated by N; and whether the cancer has metastasized to more distant parts of the body, indicated by M. Generally, if a cancer is only detectable in the area of the primary lesion without having spread to any lymph nodes it is called Stage I. If it has spread only to the closest lymph nodes, it is called Stage II. In Stage III, the cancer has generally spread to the lymph nodes in near proximity to the site of the primary lesion. Cancers that have spread to a distant part of the body, such as the liver, bone, brain or other site, are Stage IV, the most advanced stage.

The polynucleotides and corresponding genes and gene products described herein can facilitate fine-tuning of the staging process by identifying markers for the aggressiveness of a cancer, e.g. the metastatic potential, as well as the presence in different areas of the body. Thus, a Stage II cancer with a polynucleotide signifying a high metastatic potential cancer can be used to change a borderline Stage II tumor to a Stage III tumor, justifying more aggressive therapy. Conversely, the presence of a polynucleotide signifying a lower metastatic potential allows more conservative staging of a tumor.

One type of breast cancer is ductal carcinoma in situ (DCIS): DCIS is when the breast cancer cells are completely contained within the breast ducts (the channels in the breast that carry milk to the nipple), and have not spread into the surrounding breast tissue. This may also be referred to as non-invasive or intraductal cancer, as the cancer cells have not yet spread into the surrounding breast tissue and so usually have not spread into any other part of the body.

Lobular carcinoma in situ breast cancer (LCIS) means that cell changes are found in the lining of the lobules of the breast. It can be present in both breasts. It is also referred to as non-invasive cancer as it has not spread into the surrounding breast tissue.

Invasive breast cancer can be staged as follows: Stage 1 tumours: these measure less than two centimetres. The lymph glands in the armpit are not affected and there are no signs that the cancer has spread elsewhere in the body; Stage 2 tumours: these measure between two and five centimetres, or the lymph glands in the armpit are affected, or both. However, there are no signs that the cancer has spread further; Stage 3 tumours: these are larger than five centimetres and may be attached to surrounding structures such as the muscle or skin. The lymph glands are usually affected, but there are no signs that the cancer has spread beyond the breast or the lymph glands in the armpit; Stage 4 tumours: these are of any size, but the lymph glands are usually affected and the cancer has spread to other parts of the body. This is secondary breast cancer.

Grading of cancers. Grade is a term used to describe how closely a tumor resembles normal tissue of its same type. The microscopic appearance of a tumor is used to identify tumor grade based on parameters such as cell morphology, cellular organization, and other markers of differentiation. As a general rule, the grade of a tumor corresponds to its rate of growth or aggressiveness, with undifferentiated or high-grade tumors generally being more aggressive than well-differentiated or low-grade tumors.

The polynucleotides of the Sequence Listing, and their corresponding genes and gene products, can be especially valuable in determining the grade of the tumor, as they not only can aid in determining the differentiation status of the cells of a tumor, they can also identify factors other than differentiation that are valuable in determining the aggressiveness of a tumor, such as metastatic potential.

Low grade means that the cancer cells look very like the normal cells. They are usually slowly growing and are less likely to spread. In high grade tumors the cells look very abnormal. They are likely to grow more quickly and are more likely to spread.

Assessment of proliferation of cells in tumor. The differential expression level of the polynucleotides described herein can facilitate assessment of the rate of proliferation of tumor cells, and thus provide an indicator of the aggressiveness of the rate of tumor growth. For example, assessment of the relative expression levels of genes involved in cell cycle can provide an indication of cellular proliferation, and thus serve as a marker of proliferation.

Detection of Cancer.

The polynucleotides corresponding to genes that exhibit the appropriate expression pattern can be used to detect cancer in a subject. The expression of appropriate polynucleotides can be used in the diagnosis, prognosis and management of cancer. Detection of cancer can be determined using expression levels of any of these sequences alone or in combination with the levels of expression of other known cancer genes. Determination of the aggressive nature and/or the metastatic potential of a cancer can be determined by comparing levels of one or more gene products of the genes corresponding to the polynucleotides described herein, and comparing total levels of another sequence known to vary in cancerous tissue, e.g., expression of p53, DCC, ras, FAP (see, e.g., Fearon ER, et al., Cell (1990) 61(5):759; Hamilton SR et al., Cancer (1993) 72:957; Bodmer W, et al., Nat Genet. (1994) 4(3):217; Fearon E R, Ann N Y Acad Sci. (1995) 768:101). For example, development of cancer can be detected by examining the level of expression of a gene corresponding to a polynucleotides described herein to the levels of oncogenes (e.g. ras) or tumor suppressor genes (e.g. FAP or p53). Thus expression of specific marker polynucleotides can be used to discriminate between normal and cancerous tissue, to discriminate between cancers with different cells of origin, to discriminate between cancers with different potential metastatic rates, etc. For a review of other markers of cancer, see, e.g., Hanahan et al. (2000) Cell 100:57-70.

Treatment of Cancer

The invention further provides methods for reducing growth of cancer cells. The methods provide for decreasing the expression of a gene that is differentially expressed in a cancer cell or decreasing the level of and/or decreasing an activity of a cancer-associated polypeptide. In general, the methods comprise contacting a cancer cell with a substance that modulates (1) expression of a gene that is differentially expressed in cancer; or (2) a level of and/or an activity of a cancer-associated polypeptide.

“Reducing growth of cancer cells” includes, but is not limited to, reducing proliferation of cancer cells, and reducing the incidence of a non-cancerous cell becoming a cancerous cell. Whether a reduction in cancer cell growth has been achieved can be readily determined using any known assay, including, but not limited to, [³H]-thymidine incorporation; counting cell number over a period of time; detecting and/or measuring a marker associated with breast cancer (e.g., PSA).

The present invention provides methods for treating cancer, generally comprising administering to an individual in need thereof a substance that reduces cancer cell growth, in an amount sufficient to reduce cancer cell growth and treat the cancer. Whether a substance, or a specific amount of the substance, is effective in treating cancer can be assessed using any of a variety of known diagnostic assays for cancer, including, but not limited to, proctoscopy, rectal examination, biopsy, contrast radiographic studies, CAT scan, and detection of a tumor marker associated with cancer in the blood of the individual (e.g., PSA (breast-specific antigen)). The substance can be administered systemically or locally. Thus, in some embodiments, the substance is administered locally, and cancer growth is decreased at the site of administration. Local administration may be useful in treating, e.g., a solid tumor.

A substance that reduces cancer cell growth can be targeted to a cancer cell. Thus, in some embodiments, the invention provides a method of delivering a drug to a cancer cell, comprising administering a drug-antibody complex to a subject, wherein the antibody is specific for a cancer-associated polypeptide, and the drug is one that reduces cancer cell growth, a variety of which are known in the art. Targeting can be accomplished by coupling (e.g., linking, directly or via a linker molecule, either covalently or non-covalently, so as to form a drug-antibody complex) a drug to an antibody specific for a cancer-associated polypeptide. Methods of coupling a drug to an antibody are well known in the art and need not be elaborated upon herein.

Tumor Classification and Patient Stratification

The invention further provides for methods of classifying tumors, and thus grouping or “stratifying” patients, according to the expression profile of selected differentially expressed genes in a tumor. Differentially expressed genes can be analyzed for correlation with other differentially expressed genes in a single tumor type or across tumor types. Genes that demonstrate consistent correlation in expression profile in a given cancer cell type (e.g., in a cancer cell or type of cancer) can be grouped together, e.g., when one gene is overexpressed in a tumor, a second gene is also usually overexpressed. Tumors can then be classified according to the expression profile of one or more genes selected from one or more groups.

The tumor of each patient in a pool of potential patients can be classified as described above. Patients having similarly classified tumors can then be selected for participation in an investigative or clinical trial of a cancer therapeutic where a homogeneous population is desired. The tumor classification of a patient can also be used in assessing the efficacy of a cancer therapeutic in a heterogeneous patient population. In addition, therapy for a patient having a tumor of a given expression profile can then be selected accordingly.

In another embodiment, differentially expressed gene products (e.g., polypeptides or polynucleotides encoding such polypeptides) may be effectively used in treatment through vaccination. The growth of cancer cells is naturally limited in part due to immune surveillance. Stimulation of the immune system using a particular tumor-specific antigen enhances the effect towards the tumor expressing the antigen. An active vaccine comprising a polypeptide encoded by the cDNA of this invention would be appropriately administered to subjects having an alteration, e.g., overabundance, of the corresponding. RNA, or those predisposed for developing cancer cells with an alteration of the same RNA. Polypeptide antigens are typically combined with an adjuvant as part of a vaccine composition. The vaccine is preferably administered first as a priming dose, and then again as a boosting dose, usually at least four weeks later. Further boosting doses may be given to enhance the effect. The dose and its timing are usually determined by the person responsible for the treatment.

The invention also encompasses the selection of a therapeutic regimen based upon the expression profile of differentially expressed genes in the patient's tumor. For example, a tumor can be analyzed for its expression profile of the genes corresponding to SEQ ID NOS: 1-13996 as described herein, e.g., the tumor is analyzed to determine which genes are expressed at elevated levels or at decreased levels relative to normal cells of the same tissue type. The expression patterns of the tumor are then compared to the expression patterns of tumors that respond to a selected therapy. Where the expression profiles of the test tumor cell and the expression profile of a tumor cell of known drug responsivity at least substantially match (e.g., selected sets of genes at elevated levels in the tumor of known drug responsivity and are also at elevated levels in the test tumor cell), then the therapeutic agent selected for therapy is the drug to which tumors with that expression pattern respond.

Pattern Matching in Diagnosis Using Arrays

In another embodiment, the diagnostic and/or prognostic methods of the invention involve detection of expression of a selected set of genes in a test sample to produce a test expression pattern (TEP). The TEP is compared to a reference expression pattern (REP), which is generated by detection of expression of the selected set of genes in a reference sample (e.g., a positive or negative control sample). The selected set of genes includes at least one of the genes of the invention, which genes correspond to the polynucleotide sequences described herein. Of particular interest is a selected set of genes that includes gene differentially expressed in the disease for which the test sample is to be screened.

Identification of Therapeutic Targets and Anti-Cancer Therapeutic Agents

The present invention also encompasses methods for identification of agents having the ability to modulate activity of a differentially expressed gene product, as well as methods for identifying a differentially expressed gene product as a therapeutic target for treatment of cancer.

Identification of compounds that modulate activity of a differentially expressed gene product can be accomplished using any of a variety of drug screening techniques. Such agents are candidates for development of cancer therapies. Of particular interest are screening assays for agents that have tolerable toxicity for normal, non-cancerous human cells. The screening assays of the invention are generally based upon the ability of the agent to modulate an activity of a differentially expressed gene product and/or to inhibit or suppress phenomenon associated with cancer (e.g. cell proliferation, colony formation, cell cycle arrest, metastasis, and the like).

Screening of Candidate Agents

Screening assays can be based upon any of a variety of techniques readily available and known fo one of ordinary skill in the art. In general, the screening assays involve contacting a cancerous cell with a candidate agent, and assessing the effect upon biological activity of a differentially expressed gene product. The effect upon a biological activity can be detected by, for example, detection of expression of a gene product of a differentially expressed gene (e.g., a decrease in mRNA or polypeptide levels, would in turn cause a decrease in biological activity of the gene product). Alternatively or in addition, the effect of the candidate agent can be assessed by examining the effect of the candidate agent in a functional assay. For example, where the differentially expressed gene product is an enzyme, then the effect upon biological activity can be assessed by detecting a level of enzymatic activity associated with the differentially expressed gene product. The functional assay will be selected according to the differentially expressed gene product. In general, where the differentially expressed gene is increased in expression in a cancerous cell, agents of interest are those that decrease activity of the differentially expressed gene product.

Assays described infra can be readily adapted in the screening assay embodiments of the invention. Exemplary assays useful in screening candidate agents include, but are not limited to, hybridization-based assays (e.g., use of nucleic acid probes or primers to assess expression levels), antibody-based assays (e.g., to assess levels of polypeptide gene products), binding assays (e.g., to detect interaction of a candidate agent with a differentially expressed polypeptide, which assays may be competitive assays where a natural or synthetic ligand for the polypeptide is available), and the like. Additional exemplary assays include, but are not necessarily limited to, cell proliferation assays, antisense knockout assays, assays to detect inhibition of cell cycle, assays of induction of cell death/apoptosis, and the like. Generally such assays are conducted in vitro, but many assays can be adapted for in vivo analyses, e.g., in an animal model of the cancer.

Identification of Therapeutic Targets

In another embodiment, the invention contemplates identification of differentially expressed genes and gene products as therapeutic targets. In-some respects, this is the converse of the assays described above for identification of agents having activity in modulating (e.g., decreasing or increasing) activity of a differentially expressed gene product.

In this embodiment, therapeutic targets are identified by examining the effect(s) of an agent that can be demonstrated or has been demonstrated to modulate a cancerous phenotype (e.g., inhibit or suppress or prevent development of a cancerous phenotype). Such agents are generally referred to herein as an “anti-cancer agent”, which agents encompass chemotherapeutic agents. For example, the agent can be an antisense oligonucleotide that is specific for a selected gene transcript. For example, the antisense oligonucleotide may have a sequence corresponding to a sequence of a differentially expressed gene described herein, e.g., a sequence of one of SEQ ID NOS: 1-13996.

Assays for identification of therapeutic targets can be conducted in a variety of ways using methods that are well known to one of ordinary skill in the art. For example, a test cancerous cell that expresses or overexpresses a differentially expressed gene is contacted with an anti-cancer agent, the effect upon a cancerous phenotype and a biological activity of the candidate gene product assessed. The biological activity of the candidate gene product can be assayed be examining, for example, modulation of expression of a gene encoding the candidate gene product (e.g., as detected by, for example, an increase or decrease in transcript levels or polypeptide levels), or modulation of an enzymatic or other activity of the gene product. The cancerous phenotype can be, for example, cellular proliferation, loss of contact inhibition of growth (e.g., colony formation), tumor growth (in vitro or in vivo), and the like. Alternatively or in addition, the effect of modulation of a biological activity of the candidate target gene upon cell death/apoptosis or cell cycle regulation can be assessed.

Inhibition or suppression of a cancerous phenotype, or an increase in cell death or apoptosis as a result of modulation of biological activity of a candidate gene product indicates that the candidate gene product is a suitable target for cancer therapy. Assays described infra can be readily adapted for assays for identification of therapeutic targets. Generally such assays are conducted in vitro, but many assays can be adapted for in vivo analyses, e.g., in an appropriate, art-accepted animal model of the cancer.

Candidate Agents

The term “agent” as used herein describes any molecule, e.g. protein or pharmaceutical., with the capability of modulating a biological activity of a gene product of a differentially expressed gene. Generally a plurality of assay mixtures are run in parallel with different agent concentrations to obtain a differential response to the various concentrations. Typically, one of these concentrations serves as a negative control, i.e. at zero concentration or below the level of detection.

Candidate agents encompass numerous chemical classes, though typically they are organic molecules, preferably small organic compounds having a molecular weight of more than 50 and less than about 2,500 daltons. Candidate agents comprise functional groups necessary for structural interaction with proteins, particularly hydrogen bonding, and typically include at least an amine, carbonyl, hydroxyl or carboxyl group, preferably at least two of the functional chemical groups. The candidate agents often comprise cyclical carbon or heterocyclic structures and/or aromatic or polyaromatic structures substituted with one or more of the above functional groups. Candidate agents are also found among biomolecules including, but not limited to: peptides, saccharides, fatty acids, steroids, purines, pyrimidines, derivatives, structural analogs or combinations thereof.

Candidate agents are obtained from a wide variety of sources including libraries of synthetic or natural compounds. For example, numerous means are available for random and directed synthesis of a wide variety of organic compounds and biomolecules, including expression of randomized oligonucleotides and oligopeptides. Alternatively, libraries of natural compounds in the form of bacterial, fungal, plant and animal extracts (including extracts from human tissue to identify endogenous factors affecting differentially expressed gene products) are available or readily produced. Additionally, natural or synthetically produced libraries and compounds are readily modified through conventional chemical, physical and biochemical means, and may be used to produce combinatorial libraries. Known pharmacological agents may be subjected to directed or random chemical modifications, such as acylation, alkylation, esterification, amidification, etc. to produce structural analogs.

Exemplary candidate agents of particular interest include, but are not limited to, antisense and RNAi polynucleotides, and antibodies, soluble receptors, and the like. Antibodies and soluble receptors are of particular interest as candidate agents where the target differentially expressed gene product is secreted or accessible at the cell-surface (e.g., receptors and other molecule stably-associated with the outer cell membrane).

For method that involve RNAi (RNA interference), a double stranded RNA (dsRNA) molecule is usually used. The dsRNA is prepared to be substantially identical to at least a segment of a subject polynucleotide (e.g. a cDNA or gene). In general, the dsRNA is selected to have at least 70%, 75%, 80%, 85% or 90% sequence identity with the subject polynucleotide over at least a segment of the candidate gene. In other instances, the sequence identity is even higher, such as 95%, 97% or 99%, and in still other instances, there is 100% sequence identity with the subject polynucleotide over at least a segment of the subject polynucleotide. The size of the segment over which there is sequence identity can vary depending upon the size of the subject polynucleotide. In general, however, there is substantial sequence identity over at least 15, 20, 25, 30, 35, 40 or 50 nucleotides. In other instances, there is substantial sequence identity over at least 100, 200, 300, 400, 500 or 1000 nucleotides; in still other instances, there is substantial sequence identity over the entire length of the subject polynucleotide, i.e., the coding and non-coding region of the candidate gene.

Because only substantial sequence similarity between the subject polynucleotide and the dsRNA is necessary, sequence variations between these two species arising from genetic mutations, evolutionary divergence and polymorphisms can be tolerated. Moreover, as described further infra, the dsRNA can include various modified or nucleotide analogs.

Usually the dsRNA consists of two separate complementary RNA strands. However, in some instances, the dsRNA may be formed by a single strand of RNA that is self-complementary, such that the strand loops back upon itself to form a hairpin loop. Regardless of form, RNA duplex formation can occur inside or outside of a cell.

The size of the dsRNA that is utilized varies according to the size of the subject polynucleotide whose expression is to be suppressed and is sufficiently long to be effective in reducing expression of the subject polynucleotide in a cell. Generally, the dsRNA is at least 10-15 nucleotides long. In certain applications, the dsRNA is less than 20, 21, 22, 23, 24 or 25 nucleotides in length. In other instances, the dsRNA is at least 50, 100, 150 or 200 nucleotides in length. The dsRNA can be longer still in certain other applications, such as at least 300, 400, 500 or 600 nucleotides. Typically, the dsRNA is not longer than 3000 nucleotides. The optimal size for any particular subject polynucleotide can be determined by one of ordinary skill in the art without undue experimentation by varying the size of the dsRNA in a systematic fashion and determining whether the size selected is effective in interfering with expression of the subject polynucleotide.

dsRNA can be prepared according to any of a number of methods that are known in the art, including in vitro and in vivo methods, as well as by synthetic chemistry approaches.

In vitro methods. Certain methods generally involve inserting the segment corresponding to the candidate gene that is to be transcribed between a promoter or pair of promoters that are oriented to drive transcription of the inserted segment and then utilizing an appropriate RNA polymerase to carry out transcription. One such arrangement involves positioning a DNA fragment corresponding to the candidate gene or segment thereof into a vector such that it is flanked by two opposable polymerase-specific promoters that can be same or different. Transcription from such promoters produces two complementary RNA strands that can subsequently anneal to form the desired dsRNA. Exemplary plasmids for use in such systems include the plasmid (PCR 4.0 TOPO) (available from Invitrogen). Another example is the vector pGEM-T (Promega, Madison, Wis.) in which the oppositely oriented promoters are T7 and SP6; the T3 promoter can also be utilized.

In a second arrangement, DNA fragments corresponding to the segment of the subject polynucleotide that is to be transcribed is inserted both in the sense and antisense orientation downstream of a single promoter. In this system, the sense and antisense fragments are cotranscribed to generate a single RNA strand that is self-complementary and thus can form dsRNA.

Various other in vitro methods have been described. Examples of such methods include, but are not limited to, the methods described by Sadher et al. (Biochem. Int. 14:1015, 1987); by Bhattacharyya (Nature 343:484, 1990); and by Livache, et al. (U.S. Pat. No. 5,795,715), each of which is incorporated herein by reference in its entirety.

Single-stranded RNA can also be produced using a combination of enzymatic and organic synthesis or by total organic synthesis. The use of synthetic chemical methods enable one to introduce desired modified nucleotides or nucleotide analogs into the dsRNA.

In vivo methods. dsRNA can also be prepared in vivo according to a number of established methods (see, e.g., Sambrook, et al. (1989) Molecular Cloning: A Laboratory Manual, 2^(nd) ed.; Transcription and Translation (B. D. Hames, and S. J. Higgins, Eds., 1984); DNA Cloning, volumes I and II (D. N. Glover, Ed., 1985); and Oligonucleotide Synthesis (M. J. Gait, Ed., 1984, each of which is incorporated herein by reference in its entirety).

Once the single-stranded RNA has been formed, the complementary strands are allowed to anneal to form duplex RNA. Transcripts are typically treated with DNAase and further purified according to established protocols to remove proteins. Usually such purification methods are not conducted with phenol:chloroform. The resulting purified transcripts are subsequently dissolved in RNAase free water or a buffer of suitable composition.

dsRNA is generated by annealing the sense and anti-sense RNA in vitro. Generally, the strands are initially denatured to keep the strands separate and to avoid self-annealing. During the annealing process, typically certain ratios of the sense and antisense strands are combined to facilitate the annealing process. In some instances, a molar ratio of sense to antisense strands of 3:7 is used; in other instances, a ratio of 4:6 is utilized; and in still other instances, the ratio is 1:1.

The buffer composition utilized during the annealing process can in some instances affect the efficacy of the annealing process and subsequent transfection procedure. While some have indicated that the buffered solution used to carry out the annealing process should include a potassium salt such as potassium chloride (e.g. at a concentration of about 80 mM). In some embodiments, the buffer is substantially postassium free. Once single-stranded RNA has annealed to form duplex RNA, typically any single-strand overhangs are removed using an enzyme that specifically cleaves such overhangs (e.g., RNAase A or RNAase T).

Once the dsRNA has been formed, it is introduced into a reference cell, which can include an individual cell or a population of cells (e.g., a tissue, an embryo and an entire organism). The cell can be from essentially any source, including animal, plant, viral, bacterial, fungal and other sources. If a tissue, the tissue can include dividing or nondividing and differentiated or undifferentiated cells. Further, the tissue can include germ line cells and somatic cells. Examples of differentiated cells that can be utilized include, but are not limited to, neurons, glial cells, blood cells, megakaryocytes, lymphocytes, macrophages, neutrophils, eosinophils, basophils, mast cells, leukocytes, granulocytes, keratinocytes, adipocytes, osteoblasts, osteoclasts, hepatocytes, cells of the endocrine or exocrine glands, fibroblasts, myocytes, cardiomyocytes, and endothelial cells. The cell can be an individual cell of an embryo, and can be a blastocyte or an oocyte.

Certain methods are conducted using model systems for particular cellular states (e.g., a disease). For instance, certain methods provided herein are conducted with a cancer cell lines that serves as a model system for investigating genes that are correlated with various cancers.

A number of options can be utilized to deliver the dsRNA into a cell or population of cells such as in a cell culture, tissue or embryo. For instance, RNA can be directly introduced intracellularly. Various physical methods are generally utilized in such instances, such as administration by microinjection (see, e.g., Zemicka-Goetz, et al. (1997) Development 124:1133-1137; and Wianny, et al. (1998) Chromosoma 107: 430-439).

Other options for cellular delivery include permeabilizing the cell membrane and electroporation in the presence of the dsRNA, liposome-mediated transfection, or transfection using chemicals such as calcium phosphate. A number of established gene therapy techniques can also be utilized to introduce the dsRNA into a cell. By introducing a viral construct within a viral particle, for instance, one can achieve efficient introduction of an expression construct into the cell and transcription of the RNA encoded by the construct.

If the dsRNA is to be introduced into an organism or tissue, gene gun technology is an option that can be employed. This generally involves immobilizing the dsRNA on a gold particle which is subsequently fired into the desired tissue. Research has also shown that mammalian cells have transport mechanisms for taking in dsRNA (see, e.g., Asher, et al. (1969) Nature 223:715-717). Consequently, another delivery option is to administer the dsRNA extracellularly into a body cavity, interstitial space or into the blood system of the mammal for subsequent uptake by such transport processes. The lood and lymph systems and the cerebrospinal fluid are potential sites for injecting dsRNA. Oral, topical, parenteral, rectal and intraperitoneal administration are also possible modes of administration.

The composition introduced can also include various other agents in addition to the dsRNA. Examples of such agents include, but are not limited to, those that stabilize the dsRNA, enhance cellular uptake and/or increase the extent of interference. Typically, the dsRNA is introduced in a buffer that is compatible with the composition of the cell into which the RNA is introduced to prevent the cell from being shocked. The minimum size of the dsRNA that effectively achieves gene silencing can also influence the choice of delivery system and solution composition.

Sufficient dsRNA is introduced into the tissue to cause a detectable change in expression of a taget gene (assuming the candidate gene is in fact being expressed in the cell into which the dsRNA is introduced) using available detection methodologies. Thus, in some instances, sufficient dsRNA is introduced to achieve at least a 5-10% reduction in candidate gene expression as compared to a cell in which the dsRNA is not introduced. In other instances, inhibition is at least 20, 30, 40 or 50%. In still other instances, the inhibition is at least 60, 70, 80, 90 or 95%. Expression in some instances is essentially completely inhibited to undetectable levels.

The amount of dsRNA introduced depends upon various factors such as the mode of administration utilized, the size of the dsRNA, the number of cells into which dsRNA is administered, and the age and size of an animal if dsRNA is introduced into an animal. An appropriate amount can be determined by those of ordinary skill in the art by initially administering dsRNA at several different concentrations for example, for example. In certain instances when dsRNA is introduced into a cell culture, the amount of dsRNA introduced into the cells varies from about 0.5 to 3 μg per 10⁶ cells.

A number of options are available to detect interference of candidate gene expression (i.e., to detect candidate gene silencing). In general, inhibition in expression is detected by detecting a decrease in the level of the protein encoded by the candidate gene, determining the level of mRNA transcribed from the gene and/or detecting a change in phenotype associated with candidate gene expression.

Use of Polypeptides to Screen for Peptide Analogs and Antagonists

Polypeptides encoded by differentially expressed genes identified herein can be used to screen peptide libraries to identify binding partners, such as receptors, from among the encoded polypeptides. Peptide libraries can be synthesized according to methods known in the art (see, e.g., U.S. Pat. No. 5,010,175 and WO 91/17823).

Agonists or antagonists of the polypeptides of the invention can be screened using any available method known in the art, such as signal transduction, antibody binding, receptor binding, mitogenic assays, chemotaxis assays, etc. The assay conditions ideally should resemble the conditions under which the native activity is exhibited in vivo, that is, under physiologic pH, temperature, and ionic strength. Suitable agonists or antagonists will exhibit strong inhibition or enhancement of the native activity at concentrations that do not cause toxic side effects in the subject. Agonists or antagonists that compete for binding to the native polypeptide can require concentrations equal to or greater than the native concentration, while inhibitors capable of binding irreversibly to the polypeptide can be added in concentrations on the order of the native concentration.

Such screening and experimentation can lead to identification of a polypeptide binding partner, such as a receptor, encoded by a gene or a cDNA corresponding to a polynucleotide described herein, and at least one peptide agonist or antagonist of the binding partner. Such agonists and antagonists can be used to modulate, enhance, or inhibit receptor function in cells to which the receptor is native, or in cells that possess the receptor as a result of genetic engineering. Further, if the receptor shares biologically important characteristics with a known receptor, information about agonist/antagonist binding can facilitate development of improved agonists/antagonists of the known receptor.

Vaccines and Uses

The differentially expressed nucleic acids and polypeptides produced by the nucleic acids of the invention can also be used to modulate primary immune response to prevent or treat cancer. Every immune response is a complex and intricately regulated sequence of events involving several cell types. It is triggered when an antigen enters the body and encounters a specialized class of cells called antigen-presenting cells (APCs). These APCs capture a minute amount of the antigen and display it in a form that can be recognized by antigen-specific helper T lymphocytes. The helper (Th) cells become activated and, in turn, promote the activation of other classes of lymphocytes, such as B cells or cytotoxic T cells. The activated lymphocytes then proliferate and carry out their specific effector functions, which in many cases successfully activate or eliminate the antigen. Thus, activating the immune response to a particular antigen associated with a cancer cell can protect the patient from developing cancer or result in lymphocytes eliminating cancer cells expressing the antigen.

Gene products, including polypeptides, mRNA (particularly mRNAs having distinct secondary and/or tertiary structures), cDNA, or complete gene, can be prepared and used in vaccines for the treatment or prevention of hyperproliferative disorders and cancers. The nucleic acids and polypeptides can be utilized to enhance the immune response, prevent tumor progression, prevent hyperproliferative cell growth, and the like. Methods for selecting nucleic acids and polypeptides that are capable of enhancing the immune response are known in the art. Preferably, the gene products for use in a vaccine are gene products which are present on the surface of a cell and are recognizable by lymphocytes and antibodies.

The gene products may be formulated with pharmaceutically acceptable carriers into pharmaceutical compositions by methods known in the art. The composition is useful as a vaccine to prevent or treat cancer. The composition may further comprise at least one co-immunostimulatory molecule, including but not limited to one or more major histocompatibility complex (MHC) molecules, such as a class I or class II molecule, preferably a class I molecule. The composition may further comprise other stimulator molecules including B7.1, B7.2, ICAM-1, ICAM-2, LFA-1, LFA-3, CD72 and the like, immunostimulatory polynucleotides (which comprise an 5′-CG-3′ wherein the cytosine is unmethylated), and cytokines which include but are not limited to IL-1 through IL-15, TNF-α, IFN-γ, RANTES, G-CSF, M-CSF, IFN-α, CTAP III, ENA-78, GRO, 1-309, PF-4, IP-10, LD-78, MGSA, MIP-1α, MIP-1β, or combination thereof, and the like for immunopotentiation. In one embodiment, the immunopotentiators of particular interest are those that facilitate a Th1 immune response.

The gene products may also be prepared with a carrier that will protect the gene products against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid, and the like. Methods for preparation of such formulations are known in the art.

In the methods of preventing or treating cancer, the gene products may be administered via one of several routes including but not limited to transdermal, transmucosal, intravenous, intramuscular, subcutaneous, intradermal, intraperitoneal, intrathecal, intrapleural, intrauterine, rectal, vaginal, topical, intratumor, and the like. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, administration bile salts and fusidic acid derivatives. In addition, detergents may be used to facilitate permeation. Transmucosal administration may be by nasal sprays or suppositories. For oral administration, the gene products are formulated into conventional oral administration form such as capsules, tablets, elixirs and the like.

The gene product is administered to a patient in an amount effective to prevent or treat cancer. In general, it is desirable to provide the patient with a dosage of gene product of at least about 1 pg per Kg body weight, preferably at least about 1 ng per Kg body weight, more preferably at least about 1 μg or greater per Kg body weight of the recipient. A range of from about 1 ng per Kg body weight to about 100 mg per Kg body weight is preferred although a lower or higher dose mlay be administered. The dose is effective to prime, stimulate and/or cause the clonal expansion of antigen-specific T lymphocytes, preferably cytotoxic T lymphocytes, which in turn are capable of preventing or treating cancer in the recipient. The dose is administered at least once and may be provided as a bolus or a continuous administration. Multiple administrations of the dose over a period of several weeks to months may be preferable. Subsequent doses may be administered as indicated.

In another method of treatment, autologous cytotoxic lymphocytes or tumor infiltrating lymphocytes may be obtained from a patient with cancer. The lymphocytes are grown in culture, and antigen-specific lymphocytes are expanded by culturing in the presence of the specific gene products alone or in combination with at least one co-immunostimulatory molecule with cytokines. The antigen-specific lymphocytes are then infused back into the patient in an amount effective to reduce or eliminate the tumors in the patient. Cancer vaccines and their uses are further described in U.S. Pat. No. 5,961,978; U.S. Pat. No. 5,993,829; U.S. Pat. No. 6,132,980; and WO 00/38706.

Pharmaceutical Compositions and Uses

Pharmaceutical compositions can comprise polypeptides, receptors that specifically bind a polypeptide produced by a differentially expressed gene (e.g., antibodies, or polynucleotides (including antisense nucleotides and ribozymes) of the claimed invention in a therapeutically effective amount. The compositions can be used to treat primary tumors as well as metastases of primary tumors. In addition, the pharmaceutical compositions can be used in conjunction with conventional methods of cancer treatment, e.g., to sensitize tumors to radiation or conventional chemotherapy.

Where the pharmaceutical composition comprises a receptor (such as an antibody) that specifically binds to a gene product encoded by a differentially expressed gene, the receptor can be coupled to a drug for delivery to a treatment site or coupled to a detectable label to facilitate imaging of a site comprising cancer cells. Methods for coupling antibodies to drugs and detectable labels are well known in the art, as are methods for imaging using detectable labels.

The term “therapeutically effective amount” as used herein refers to an amount of a therapeutic agent to treat, ameliorate, or prevent a desired disease or condition, or to exhibit a detectable therapeutic or preventative effect. The effect can be detected by, for example, chemical markers or antigen levels. Therapeutic effects also include reduction in physical symptoms, such as decreased body temperature.

The precise effective amount for a subject will depend upon the subject's size and health, the nature and extent of the condition, and the therapeutics or combination of therapeutics selected for administration. Thus, it is not useful to specify an exact effective amount in advance. However, the effective amount for a given situation is determined by routine experimentation and is within the judgment of the clinician. For purposes of the present invention, an effective dose will generally be from about 0.01 mg/ kg to 50 mg/kg or 0.05 mg/kg to about 10 mg/kg of the DNA constructs in the individual to which it is administered.

A pharmaceutical composition can also contain a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable carrier” refers to a carrier for administration of a therapeutic agent, such as antibodies or a polypeptide, genes, and other therapeutic agents. The term refers to any pharmaceutical carrier that does not itself induce the production of antibodies harmful to the individual receiving the composition, and which can be administered without undue toxicity. Suitable carriers can be large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, lipid aggregates and inactive virus particles. Such carriers are well known to those of ordinary skill in the art. Pharmaceutically acceptable carriers in therapeutic compositions can include liquids such as water, saline, glycerol and ethanol. Auxiliary substances, such as wetting or emulsifying agents, pH buffering substances, and the like, can also be present in such vehicles.

Typically, the therapeutic compositions are prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection can also be prepared. Liposomes are included within the definition of a pharmaceutically acceptable carrier. Pharmaceutically acceptable salts can also be present in the pharmaceutical composition, e.g., mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, and the like; and the salts of organic acids such as acetates, propionates, malonates, benzoates, and the like. A thorough discussion of pharmaceutically acceptable excipients is available in Remington: The Science and Practice of Pharmacy (1995) Alfonso Gennaro, Lippincott, Williams, & Wilkins.

Delivery Methods

Once formulated, the compositions contemplated by the invention can be (1) administered directly to the subject (e.g., as polynucleotide, polypeptides, small molecule agonists or antagonists, and the like); or (2) delivered ex vivo, to cells derived from the subject (e.g., as in ex vivo gene therapy). Direct delivery of the compositions will generally be accomplished by parenteral injection, e.g., subcutaneously, intraperitoneally, intravenously or intramuscularly, intratumoral or to the interstitial space of a tissue. Other modes of administration include oral and pulmonary administration, suppositories, and transdermal applications, needles, and gene guns or hyposprays. Dosage treatment can be a single dose schedule or a multiple dose schedule.

Methods for the ex vivo delivery and reimplantation of transformed cells into a subject are known in the art and described in e.g., International Publication No. WO 93/14778. Examples of cells useful in ex vivo applications include, for example, stem cells, particularly hematopoetic, lymph cells, macrophages, dendritic cells, or tumor cells. Generally, delivery of nucleic acids for both ex vivo and in vitro applications can be accomplished by, for example, dextran-mediated transfection, calcium phosphate precipitation, polybrene mediated transfection, protoplast fusion, electroporation, encapsulation of the polynucleotide(s) in liposomes, and direct microinjection of the DNA into nuclei, all well known in the art.

Once differential expression of a gene corresponding to a polynucleotide described herein has been found to correlate with a proliferative disorder, such as neoplasia, dysplasia, and hyperplasia, the disorder can be amenable to treatment by administration of a therapeutic agent based on the provided polynucleotide, corresponding polypeptide or other corresponding molecule (e.g., antisense, ribozyme, etc.). In other embodiments, the disorder can be amenable to treatment by administration of a small molecule drug that, for example, serves as an inhibitor (antagonist) of the function of the encoded gene product of a gene having increased expression in cancerous cells relative to normal cells or as an agonist for gene products that are decreased in expression in cancerous cells (e.g., to promote the activity of gene products that act as tumor suppressors).

The dose and the means of administration of the inventive pharmaceutical compositions are determined based on the specific qualities of the therapeutic composition, the condition, age, and weight of the patient, the progression of the disease, and other relevant factors. For example, administration of polynucleotide therapeutic composition agents includes local or systemic administration, including injection, oral administration, particle gun or catheterized administration, and topical administration. In general, the therapeutic polynucleotide composition contains an expression construct comprising a promoter operably linked to a polynucleotide of at least 12, 22, 25, 30, or 35 contiguous nt of the polynucleotide disclosed herein. Various methods can be used to administer the therapeutic composition directly to a specific site in the body. For example, a small metastatic lesion is located and the therapeutic composition injected several times in several different locations within the body of the tumor. Alternatively, arteries which serve a tumor are identified, and the therapeutic composition injected into such an artery, in order to deliver the composition directly into the tumor. A tumor that has a necrotic center is aspirated and the composition injected directly into the now empty center of the tumor. The antisense composition is directly administered to the surface of the tumor, for example, by topical application of the composition. X-ray imaging is used to assist in certain of the above delivery methods.

Targeted delivery of therapeutic compositions containing an antisense polynucleotide, subgenomic polynucleotides, or antibodies to specific tissues can also be used. Receptor-mediated DNA delivery techniques are described in, for example, Findeis et al., Trends Biotechnol. (1993) 11:202; Chiou et al., Gene Therapeutics: Methods And Applications Of Direct Gene Transfer (J. A. Wolff, ed.) (1994); Wu et al., J. Biol. Chem. (1988) 263:621; Wu et al., J. Biol. Chem. (1994) 269:542; Zenke et al., Proc. Natl. Acad. Sci. (USA) (1990) 87:3655; Wu et al., J. Biol. Chem. (1991) 266:338. Therapeutic compositions containing a polynucleotide are administered in a range of about 100 ng to about 200 mg of DNA for local administration in a gene therapy protocol. Concentration ranges of about 500 ng to about 50 mg, about 1 μg to about 2 mg, about 5 μg to about 500 pg, and about 20 μg to about 100 :g of DNA can also be used during a gene therapy protocol. Factors such as method of action (e.g., for enhancing or inhibiting levels of the encoded gene product) and efficacy of transformation and expression are considerations that will affect the dosage required for ultimate efficacy of the antisense subgenomic polynucleotides.

The therapeutic polynucleotides and polypeptides of the present invention can be delivered using gene delivery vehicles. The gene delivery vehicle can be of viral or non-viral origin (see generally, Jolly, Cancer Gene Therapy (1994) 1:51; Kimura, Human Gene Therapy (1994) 5:845; Connelly, Human Gene Therapy (1995) 1:185; and Kaplitt, Nature Genetics (1994) 6:148). Expression of such coding sequences can be induced using endogenous mammalian or heterologous promoters. Expression of the coding sequence can be either constitutive or regulated.

Viral-based vectors for delivery of a desired polynucleotide and expression in a desired cell are well known in the art. Exemplary viral-based vehicles include, but are not limited to, recombinant retroviruses (see, e.g., WO 90/07936; WO 94/03622; WO 93/25698; WO 93/25234; U.S. Pat. No. 5,219,740; WO 93/11230; WO 93/10218; U.S. Pat. No. 4,777,127; GB Patent No. 2,200,651; EP 0 345 242; and WO 91/02805), alphavirus-based vectors (e.g., Sindbis virus vectors, Semliki forest virus (ATCC VR-67; ATCC VR-1247), Ross River virus (ATCC VR-373; ATCC VR-1246) and Venezuelan equine encephalitis virus (ATCC VR-923; ATCC VR-1250; ATCC VR 1249; ATCC VR-532), and adeno-associated virus (AAV) vectors (see, e.g., WO 94/12649, WO 93/03769; WO 93/19191; WO 94/28938; WO 95/11984 and WO 95/00655). Administration of DNA linked to killed adenovirus as described in Curiel, Hum. Gene Ther. (1992) 3:147 can also be employed.

Non-viral delivery vehicles and methods can also be employed, including, but not limited to, polycationic condensed DNA linked or unlinked to killed adenovirus alone (see, e.g., Curiel, Hum. Gene Ther. (1992) 3:147); ligand-linked DNA (see, e.g., Wu, J. Biol. Chem. (1989) 264:16985); eukaryotic cell delivery vehicles cells (see, e.g., U.S. Pat. No. 5,814,482; WO 95/07994; WO 96/17072; WO 95/30763; and WO 97/42338) and nucleic charge neutralization or fusion with cell membranes. Naked DNA can also be employed. Exemplary naked DNA introduction methods are described in WO 90/11092 and U.S. Pat. No. 5,580,859. Liposomes that can act as gene delivery vehicles are described in U.S. Pat. No. 5,422,120; WO 95/13796; WO 94/23697; WO 91/14445; and EP 0524968. Additional approaches are described in Philip, Mol. Cell Biol. (1994) 14:2411, and in Woffendin, Proc. Natl. Acad. Sci. (1994) 91:1581.

Tumor Classification and Patient Stratification

The invention further provides for methods of classifying tumors, and thus grouping or “stratifying” patients, according to the expression profile of selected differentially expressed genes in a tumor. The expression patterns of differentially expressed genes can be analyzed for correlation with the expression patterns of other differentially expressed genes in a single tumor type or across tumor types. Genes that demonstrate consistent correlation can be grouped together, e.g., genes are grouped together where if one gene is overexpressed in a tumor, a second gene is also usually overexpressed. Tumors can then be classified according to the expression profile of one or more genes selected from one or more groups.

For example, a colon tumor can be classified according to expression level of a gene product of one or more genes selected from one or more of the following groups: 1) Group I, which comprises the genes IGF2, TTK, MAPKAPK2, MARCKS, BBS2, CETN2 CGI-148 protein, FGFR4, FHL3, FLJ22066, KIP2, MGC:29604, NQO2, and OGG1; and 2) Group II, which comprises the genes IFITM (I-8U; 1-8D; 9-27), ITAK, and BIRC3/H-IAP 1.

A Group I-type colon tumor has increased expression of at least one, usually at least two, more usually at least three, even more usually at least four, preferably at least five, more preferably at least six or more, but usually not more than 12, 10, or 8, Group I genes relative to a non-cancerous colon cell, where the expression is increased at least about 1.5-fold, at least about 2-fold, at least about 5-fold, or at least about 10-fold, and can be as high 50-fold, but is usually not more than 20-fold or 30-fold.

A Group II-type colon tumor is increased in expression of at least one, usually at least two, more usually at least three, Group II genes relative to a non-cancerous colon cells, where the expression is increased at least about 1.5-fold, at least about 2-fold, at least about 5-fold, or at least about 10-fold, and can be as high 50-fold, but is usually not more than 20-fold or 30-fold.

A Group I+II-type colon tumor is increased in expression of at least one, usually at least two, more usually at least three, even more usually at least four, preferably at least five, more preferably at least six or more, but usually not more than 12, 10, or 8, Group I genes relative to a non-cancerous colon cell, and has increased expression of at least one, usually at least two, more usually at least three, Group II genes relative to a non-cancerous colon cells, where expression of both the Group I and Group II genes is increased at least about 1.5-fold, at least about 2-fold, at least about 5-fold, or at least about 10-fold, and can be as high 50-fold, but is usually not more than 20-fold or 30-fold.

The tumor of each patient in a pool of potential patients for a clinical trial can be classified as described above. Patients having similarly classified tumors can then be selected for participation in an investigative or clinical trial of a cancer therapeutic where a homogeneous population is desired. The tumor classification of a patient can also be used in assessing the efficacy of a cancer therapeutic in a heterogeneous patient population. Thus, comparison of an individual's expression profile to the population profile for a type of cancer, permits the selection or design of drugs or other therapeutic regimens that are expected to be safe and efficacious for a particular patient or patient population (i.e., a group of patients having the same type of cancer).

In addition, the ability to target populations expected to show the most clinical benefit, based on expression profile can enable: 1) the repositioning of already marketed drugs; 2) the rescue of drug candidates whose clinical development has been discontinued as a result of safety or efficacy limitations, which are patient subgroup-specific; and 3) an accelerated and less costly development for candidate therapeutics and more optimal drug labeling (e.g. since measuring the effect of various doses of an agent on patients with a particular expression profile is useful for optimizing effective dose).

A certain embodiment of the invention is based on the discovery of genes differentially expressed in cancerous colon cells relative to normal cells, particularly metastatic or pre-metastatic cancerous colon cells relative to normal cells of the same tissue type. The genes of particular interest are those described in the Examples below. The invention is further based on the discovery that colon tumors can be classified according to the expression pattern of one or more of genes, and that patients can thus be classified and diagnosed, and therapy selected accordingly, according to these expression patterns. The gene(s) for analysis of expression of a gene product encoded by at least one gene selected from at least one of the following groups: 1) Group I, which comprises the genes IGF2, TTK, MAPKAPK2, MARCKS, BBS2, CETN2 CGI-148 protein, FGFR4, FHL3, FLJ22066, KIP2, MGC:29604, NQO2, and OGGI; and 2) Group II, which comprises the genes IFITM (I-8U; 1-8D; 9-27), ITAK, and BIRC3/H-IAP1. A tumor can then be classified as a Group I-type, Group II-type, or Group I+II-type tumor based on the expression profile of the tumor. The expression patterns associated with colon cancer, and which provide the basis for tumor classification and patient stratification, are described in the Examples below.

The methods of the invention can be carried out using any suitable probe for detection of a gene product that is differentially expressed in colon cancer cells. For example, mRNA (or cDNA generated from mRNA) expressed from a differentially expressed gene can be detected using polynucleotide probes. In another example, the differentially expressed gene product is a polypeptide, which polypeptides can be detected using, for example, antibodies that specifically bind such polypeptides or an antigenic portion thereof.

The present invention relates to methods and compositions useful in diagnosis of colon cancer, design of rational therapy, and the selection of patient populations for the purposes of clinical trials. The invention is based on the discovery that colon tumors of a patient can be classified according to an expression profile of one or more selected genes, which genes are differentially expressed in tumor cells relative to normal cells of the same tissue. Polynucleotides that correspond to the selected differentially expressed genes can be used in diagnostic assays to provide for diagnosis of cancer at the molecular level, and to provide for the basis for rational therapy (e.g., therapy is selected according to the expression pattern of a selected set of genes in the tumor). The gene products encoded by differentially expressed genes can also serve as therapeutic targets, and candidate agents effective against such targets screened by, for example, analyzing the ability of candidate agents to modulate activity of differentially expressed gene products.

In one aspect, the selected gene(s) for tumor cell (and thus patient) analysis of expression of a gene product encoded by at least one gene selected from at least one of the following groups: 1) Group I, which comprises the genes IGF2, TTK, MAPKAPK2, MARCKS, BBS2, CETN2 CGI-148 protein, FGFR4, FHL3, FLJ22066, KIP2, MGC:29604, NQO2, and OGGI; and 2) Group II, which comprises the genes IFITM (1-8U; 1-8D; 9-27), ITAK, and BIRC3/H-IAP1.

In another aspect, the invention provides a method for classifying a tumor that shares selected characteristics with respect to a tumor expression profile. In one embodiment, the invention provides a method for classifying a tumor according to an expression profile of one or more genes comprising detecting expression of at least a first Group I gene in a test colon cell sample. Detection of increased expression of the first gene in the test colon cell sample relative to expression of the gene in a control non-cancer cell sample indicates that the tumor is a Group I-type tumor.

In one embodiment, the first Group I gene is an IGF2 gene. In other specific embodiments, the method further comprises detecting expression of a second Group I gene in the test colon cell sample. Detection of increased expression of the first and second genes in the test colon cell sample relative to expression of the first and second genes, respectively, in a control non-cancer cell sample indicates that the tumor is a Group I-type tumor.

In another embodiment, the method further comprises detecting expression of a second and third Group I gene in the test colon cell sample. Detection of increased expression of the first, second, and third genes in the test colon cell sample relative to expression of the first, second, and third genes, respectively, in a control non-cancer cell sample indicates that the tumor is a Group I-type tumor. In other embodiments, the expression of the gene(s) is increased about 1.5-fold, about 2-fold, about 5-fold, or about 10-fold in the test sample relative to the control sample.

In another embodiment, the invention provides a method for classifying a tumor according to an expression profile of one or more genes comprising detecting expression of at least a first Group II gene in a test colon cell sample. Detection of increased expression of the first gene in the test colon cell sample relative to expression of the gene in a control non-cancer cell sample indicates that the tumor is a Group II-type tumor.

In another embodiment, the first Group II gene is a member of the IF ITM family of genes. In other specific embodiments, the method further comprises detecting expression of a second Group II gene in the test colon cell sample. Detection of increased expression of the first and second genes in the test colon cell sample relative to expression of the first and second genes, respectively, in a control non-cancer cell sample indicates that the tumor is a Group II-type tumor. In other embodiments, the expression of the gene(s) is increased about 1.5-fold, about 2-fold, about 5-fold, or about 10-fold in the test sample relative to the control sample. In yet other specific embodiments, the first Group II gene is 1-8U, 1-8D, or 9-27.

In another embodiment, the invention provides a method for classifying a tumor according to an expression profile of two or more genes, the method comprising analyzing a test colon cell sample for expression of at least one Group I gene and at least one Group II gene. Detection of increased expression of the at least one Group I gene and the at least one Group II gene in the test cell sample relative to expression of the at least one Group I gene and the at least one Group II gene, respectively, in a control non-cancer cell sample indicates the tumor is a Group I+II-type tumor. In other embodiments, the Group I gene is an IGF2 gene and the Group II gene is a member of the IFITM family of genes. In yet other embodiments, the expression of the genes is increased about 1.5-fold, about 2-fold, about 5-fold, or about 10-fold in the test sample relative to the control sample.

In another aspect, the invention provides methods for selection of a patient population having a tumor that shares selected characteristics, with respect to a tumor expression profile. This method, referred to herein as “patient stratification,” can be used to improve the design of a clinical trial by providing a patient population that is more homogenous with respect to the tumor type that is to be tested for responsiveness to a new therapy; and in selecting the best therapeutic regiment for a patient in view of an expression profile of the subject's tumor (e.g., rational therapy).

In another aspect, the invention provides a method for selecting an individual for inclusion in a clinical trial, the method comprising the steps of: detecting a level of expression of a gene product in a test colon cell sample or serum obtained from a subject, the gene product being encoded by at least one gene selected from the group consisting of IGF2, TTK, MAPKAPK2, MARCKS, BBS2, CETN2 CGI-148 protein, FGFR4, FHL3, FLJ22066, KIP2, MGC:29604, NQO2, and OGGI; and comparing the level of expression of the gene product in the test sample to a level of expression in a normal colon cell; wherein detection of a level of expression of the gene product that is significantly higher in the test sample than in a normal cell is a positive indicator for inclusion of the subject in the test population for the clinical trial.

In another aspect the invention provides a method for selecting an individual for inclusion in a clinical trial, the method comprising the steps of: detecting a level of expression of a gene product in a test colon cell sample obtained from a subject, the gene product being encoded by at least one gene selected from the group consisting of: IFITM 1-8U; 1-8D; 9-27), ITAK, and BIRC3/H-IAP1; and comparing the level of expression of the gene product in the test sample to a level of expression in a normal colon cell; wherein detection of a level of expression of the gene product that is significantly higher in the test sample than in a normal cell is a positive indicator for inclusion of the subject in the test population for the clinical trial.

In related aspects the invention provides methods of reducing growth of cancerous colon cells by modulation of expression of one or more gene products corresponding to a gene selected from: 1) Group I, which comprises the genes IGF2, TTK, MAPKAPK2, MARCKS, BBS2, CETN2 CGI-148 protein, FGFR4, FHL3, FLJ22066, KIP2, MGC:29604, NQO2, and OGGI; and 2) Group II, which comprises the genes IFITM (I-8U; 1-8D; 9-27), ITAK, and BIRC3/H-IAPI. These methods are useful for treating colon cancer.

In another aspect, the present invention provides methods for disease detection by analysis of gene expression. In general, diagnostic and prognostic methods of the invention can involve obtaining a test cell from a subject, e.g., colon cells; detecting the level of expression of any one gene or a selected set of genes in the test cell, where the gene(s) are differentially expressed in a colon tumor cell relative to a normal colon cell; and comparing the expression levels of the gene(s) in the test cell to a control level (e.g., a level of expression in a normal (non-cancerous) colon cell). Detection of a level of expression in the test cell that differs from that found in a normal cell indicates that the test cell is a cancerous cell. The method of the invention permits, for example, detection of a small increase or decrease in gene product production from a gene whose overexpression or underexpression (compared to a reference gene) is associated with cancer or the predisposition for a cancer.

In another aspect the invention provides a method for detecting a cancerous colon cell comprising contacting a sample obtained from a test colon cell with a probe for detection of a gene product of a gene differentially expressed in colon cancer, wherein the gene corresponds to a polynucleotide having a sequence selected from the group consisting of SEQ ID NOS: 1-20, and where contacting is for a time sufficient for binding of the probe to the gene product; and comparing a level of binding of the probe to the sample with a level of probe binding to a control sample obtained from a control colon cell, wherein the control colon cell is of known cancerous state. An increased level of binding of the probe in the test colon cell sample relative to the level of binding in a control sample is indicative of the cancerous state of the test colon cell. In specific embodiments, the probe is a polynucleotide probe and the gene product is nucleic acid. In other specific embodiments, the gene product is a polypeptide. In further embodiments, the gene product or the probe is immobilized on an array.

In another aspect, the invention provides a method for assessing the cancerous phenotype (e.g., metastasis, aberrant cellular proliferation, and the like) of a colon cell comprising detecting expression of a gene product in a test colon cell sample, wherein the gene comprises a sequence selected from the group consisting of SEQ ID NOS: 1-20; and comparing a level of expression of the gene product in the test colon cell sample with a level of expression of the gene in a control cell sample. Comparison of the level of expression of the gene in the test cell sample relative to the level of expression in the control cell sample is indicative of the cancerous phenotype of the test cell sample. In specific embodiments, detection of expression of the gene is by detecting a level of an RNA transcript in the test cell sample. In other specific embodiments detection of expression of the gene is by detecting a level of a polypeptide in a test sample.

In another aspect, the invention provides a method for suppressing or inhibiting a cancerous phenotype of a cancerous cell, the method comprising introducing into a mammalian cell an antisense polynucleotide for inhibition of expression of a gene comprising a sequence selected from the group consisting of SEQ ID NOS: 1-20. Inhibition of expression of the gene inhibits development of a cancerous phenotype in the cell. In specific embodiments, the cancerous phenotype is metastasis, aberrant cellular proliferation relative to a normal cell, or loss of contact inhibition of cell growth.

In another aspect, the invention provides a method for assessing the tumor burden of a subject, the method comprising detecting a level of a differentially expressed gene product in a test sample from a subject suspected of or having a tumor, the differentially expressed gene product comprising a sequence selected from the group consisting of SEQ ID NOS: 1-20. Detection of the level of the gene product in the test sample is indicative of the tumor burden in the subject.

In another aspect, the invention provides a method for identifying a gene product as a target for a cancer therapeutic, the method comprising contacting a cancerous cell expressing a candidate gene product with an anti-cancer agent, wherein the candidate gene product corresponds to a sequence selected from the group consisting of SEQ ID NOS: 1-20; and analyzing the effect of the anti-cancer agent upon a biological activity of the candidate gene product and upon a cancerous phenotype of the cancerous cell. Modulation of the biological activity of the candidate gene product and modulation of the cancerous phenotype of the cancerous cell indicates the candidate gene product is a target for a cancer therapeutic. In specific embodiments, the cancerous cell is a cancerous colon cell. In other specific embodiments, the inhibitor is an antisense oligonucleotide. In further embodiments, the cancerous phenotype is aberrant cellular proliferation relative to a normal cell, or colony formation due to loss of contact inhibition of cell growth.

In another aspect, the invention provides a method for identifying agents that decrease biological activity of a gene product differentially expressed in a cancerous cell, the method comprising contacting a candidate agent with a differentially expressed gene product, the differentially expressed gene product corresponding to a sequence selected from the group consisting of SEQ ID NOS: 1-20; and detecting a decrease in a biological activity of the gene product relative to a level of biological activity of the gene product in the absence of the candidate agent. In specific embodiments, the detecting is by detection of a decrease in expression of the differentially expressed gene product. In other specific embodiments, the gene product is mRNA or cDNA prepared from the mRNA gene product. In further embodiments, the gene product is a polypeptide.

In all embodiments of the invention, analysis of expression of a gene product of a selected gene can be accomplished by analysis of gene transcription (e.g., by generating cDNA clones from mRNAs isolated from a cell suspected of being cancerous and comparing the number of cDNA clones corresponding to the gene in the sample relative to a number of clones present in a non-cancer cell of the same tissue type), detection of an encoded gene product (e.g., assessing a level of polypeptide encoded by a selected gene present in the test cell suspected of being cancerous relative to a level of the polypeptide in a non-cancer cell of the same tissue type), detection of a biological activity of a gene product encoded by a selected gene, and the like.

In all embodiments of the invention, comparison of gene product expression of a selected gene in a tumor cell can involve, for example, comparison to an “internal” control cell (e.g., a non-cancer cell of the same tissue type obtained from the same patient from whom the sample suspected of having a tumor cell was obtained), comparison to a control cell analyzed in parallel in the assay (e.g., a non-cancer cell, normally of the same tissue type as the test cell or a cancerous cell, normally of the same tissue type as the test cell), or comparison to a level of gene product expression known to be associated with a normal cell or a cancerous cell, normally of the same tissue type (e.g., a level of gene product expression is compared to a known level or range of levels of gene product expression for a normal cell or a cancerous cell, which can be provided in the form of, for example, a standard).

The sequences disclosed in this patent application were disclosed in several earlier patent applications. The relationship between the SEQ ID NOS in those earlier application and the SEQ ID NOS disclosed herein is shown in Tables 68. TABLE 68 relationship between SEQ ID NOs. this patent application and SEQ ID NOs of parent patent applications SEQ corresponding parent IDs in SEQ IDs application parent in this patent parent case no. filing date case application 15805CON 10/616,900 Jul. 9, 2003 1-321  1-321 16335 10/081,519 Feb. 21, 2002 1-20  322-341 18095 10/310,673 Dec. 4, 2002  1-2164  342-2505 17767 10/501,187 Jul. 8, 2004 1-516 2506-3021 16336 10/081,124 Feb. 21, 2002  1-1303 3022-4324 18376 US04/15421 May 13, 2004  1-9672  4325-13996

The disclosures of all prior U.S. applications to which the present application claims priority, which includes those U.S. applications referenced in the table above as well as their respective priority applications, are each incorporated herein by referenced in their entireties for all purposes, including the disclosures found in the Sequence Listings, tables, figures and Examples.

EXAMPLES

The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric.

Example 1 Source of Biological Materials and Isolation of Polynucleotides Expressed by the Biological Materials

Candidate polynucleotides that may represent genes differentially expressed in cancer were obtained from both publicly available sources and from cDNA libraries generted from selected cell lines and patient tissues. In order to obtain the latter ploynucleotides, mRNA was isolated from several selected cell lines and patient tissues, and used to construct cDNA libraries. The cells and tissues that served as sources for these CDNA libraries are summarized in Table 1 below. TABLE 1 Description of cDNA Libraries Number of Library Clones in (lib #) Description Library 1 Human Colon Cell Line Km12 L4: High Metastatic 308731 Potential (derived from Km12C) 2 Human Colon Cell Line Km12C: Low Metastatic 284771 Potential 3 Human Breast Cancer Cell Line MDA-MB-231: 326937 High Metastatic Potential; micro-mets in lung 4 Human Breast Cancer Cell Line MCF7: Non 318979 Metastatic 8 Human Lung Cancer Cell Line MV-522: High 223620 Metastatic Potential 9 Human Lung Cancer Cell Line UCP-3: Low 312503 Metastatic Potential 12 Human microvascular endothelial cells (HMVEC) - 41938 UNTREATED (PCR (OligodT) cDNA library) 13 Human microvascular endothelial cells (HMVEC) - 42100 bFGF TREATED (PCR (OligodT) cDNA library) 14 Human microvascular endothelial cells (HMVEC) - 42825 VEGF TREATED (PCR (OligodT) cDNA library) 15 Normal Colon - UC#2 Patient (MICRODISSECTED 248436 PCR (OligodT) cDNA library) 16 Colon Tumor - UC#2 Patient (MICRODISSECTED 263206 PCR (OligodT) cDNA library) 17 Liver Metastasis from Colon Tumor of UC#2 266482 Patient (MICRODISSECTED PCR (OligodT) cDNA library) 18 Normal Colon - UC#3 Patient (MICRODISSECTED 36216 PCR (OligodT) cDNA library) 19 Colon Tumor - UC#3 Patient (MICRODISSECTED 41388 PCR (OligodT) cDNA library) 20 Liver Metastasis from Colon Tumor of UC#3 30956 Patient (MICRODISSECTED PCR (OligodT) cDNA library) 21 GRRpz Cells derived from normal 164801 prostate epithelium 22 WOca Cells derived from Gleason Grade 4 prostate 162088 cancer epithelium 23 Normal Lung Epithelium of Patient #1006 306197 (MICRODISSECTED PCR (OligodT) cDNA library) 24 Primary tumor, Large Cell Carcinoma of Patient 309349 #1006 (MICRODISSECTED PCR (OligodT) cDNA library)

The human colon cancer cell line Kml2L4-A (Morikawa, et al., Cancer Research (1988) 6863) is derived from the KM12C cell line. The KM12C cell line (Morikawa et. al Cancer Res. (1988) 48:1943-1948), which is poorly metastatic (low metastatic) was established in culture from a Dukes stage B2 surgical specimen (Morikawa et al. Cancer Res. (1988) 48:6863). The KML4-A is a highly metastatic subline derived from KM12C (Yeatman et al. Nucl. Acids. Res. (1995) 23:4007; Bao-Ling et al. Proc. Annu. Meet. Am. Assoc. Cancer. Res. (1995) 21:3269). The KM12C and KM12C-derived cell lines (e.g., KM12L4, KM12L4-A, etc.) are well-recognized in the art as a model cell line for the study of colon cancer (see, e.g., Moriakawa et al., supra; Radinsky et al. Clin. Cancer Res. (1995) 1:19; Yeatman et al., (1995) supra; Yeatman et al. Clin. Exp. Metastasis (1996)14:246).

The MDA-MB-231 cell line (Brinkley et al. Cancer Res. (1980) 40:3118-3129) was originally isolated from pleural effusions (Cailleau, J. Natl. Cancer. Inst. (1974) 53;661) is of high metastatic potential, and forms poorly differentiated adenocarcinoma grage II in nude mice consistent with breast carcinoma. The MCF7 cell line was derived from a pleural effusion of a breast adenocarcinoma and is non-metastatic. The MV-522 cell line is derived from a human lung carcinoma and is of high metastatic potential. The UCP-3 cell line is a low metastatic human lung carcinoma cell line; the MV-522 is a high metastatic variant of UCP-3. These cell lines are well-recognized in the art as models for the study of human breast and lung cancer (see, e.g., Chandrasekaran et al., Cancer Res. (1979) 9:870 (MDA-MB-231 and MCF-7); Gastpar et al., J Med Chem (1998) 41:4965 MDA-MB-231 and MCF-7); Ranson et al., Br J Cancer (1998) 77:1586 (MDA-MB-231 and MCF-7); Kuang et al., Nucleic Acids Res (1998) 26:1116 (MDA-MB-231 and MCF-7); Varki et al., Int J Cancer (1987) 40:46 (UCP-3); Varki etal., Tumour Biol. (1990) 11:327; (MV-522 and UCP-3); Varki et al., Anticancer Res. (1990) 10:637; (MV-522); Kelner et al., Anticancer Res (1995) 15:867 (MV-522); and Zhang et al., Anticancer Drugs (1997) 8:696 (MV522)).

The samples of libraries 15-20 are derived from two different patients (UC#2, and UC#3). The bFGF-treated HMVEC were prepared by incubation with bFGF at 10 ng/ml for 2 hrs; the VEGF-treated HMVEC were prepared by incubation with 20 ng/ml VEGF for 2 hrs. Following incubation with the respective growth factor, the cells were washed and lysis buffer added for RNA preparation. The GRRpz and WOca cell lines were provided by Dr. Donna M. Peehl, Department of Medicine, Stanford University School of Medicine. GRRpz was derived from normal prostate epithelium. The WOca cell line is a Gleason Grade 4 cell line.

Characterization of Sequences in the Libraries

The sequences of the isolated polynucleotides were first masked to eliminate low complexity sequences using the XBLAST masking program (Claverie “Effective Large-Scale Scale Sequence Similarity Searches,” In: Computer Methods for Macromolecular Sequence Analysis, Doolittle, ed., Meth. Enzymol. 266:212-227 Academic Press, NY, N.Y. (1996); see particularly Claverie, in “Automated DNA Sequencing and Analysis Techniques” Adams et al., eds., Chap. 36, p. 267 Academic Press, San Diego, 1994 and Claverie et al. Comput. Chem. (1993) 17:191 ). Generally, masking does not influence the final search results, except to eliminate sequences of relative little interest due to their low complexity, and to eliminate multiple “hits” based on similarity to repetitive regions common to multiple sequences, e.g., Alu repeats. Masking resulted in the elimination of several sequences. The remaining sequences were then used in a BLASTN vs. GenBank search. Gene assignment for the query sequences was determined based on best hit from the GenBank database; expectancy values are provided with the hit.

Summary of Polynucleotides Described Herein

Table 2 (inserted before the claims) provides a summary of polynucleotides isolated as described above and identified as corresponding to a differentially expressed gene (see Example 2 below), as well as those polynucleotides obtained from publicly available sources. Specifically, Table 2 provides: 1) the SEQ ID NO assigned to each sequence for use in the present specification; 2) the Candidate Identification Number (“CID”) to which the sequence is assigned and which number is based on the selection of the candidate for further evaluation in the differential expression in cancerous cells relative to normal cells; 3) the Sequence Name assigned to each sequence; and 4) the name assigned to the sample or clone from which the sequence was isolated. The sequences corresponding to SEQ ID NOS are provided in the Sequence Listing. Because at least some of the provided polynucleotides represent partial mRNA transcripts, two or more polynucleotides may represent different regions of the same mRNA transcript and the same gene and/or may be contained within the same clone. Thus, if two or more SEQ ID NOS are identified as belonging to the same clone, then either sequence can be used to obtain the full-length mRNA or gene. It should be noted that not all cDNA libraries described above are represented on an array in the examples described below. TABLE 2 SEQ ID NO CID Sequence Name Sample Name or Clone Name 1 114 016824.Seq M00003814C:C11 2 123 019.G3.sp6_128473 M00006883D:H12 3 114 020.B11.sp6_128613 M00003814C:C11 4 1 1222317 I:1222317:15A02:C02 5 2 1227385 I:1227385:14B01:G05 6 3 1297179 I:1297179:05A02:F02 7 4 1298021 I:1298021:05A01:G10 8 5 1358285 I:1358285:04A02:F11 9 6 1384823 I:1384823:01B02:F08 10 7 1395918 I:1395918:04A01:G10 11 8 1402615 I:1402615:09A02:E03 12 9 1421929 I:1421929:05A01:D02 13 10 1431819 I:1431819:14B01:D05 14 11 1443877 I:1443877:03B02:B08 15 12 1450639 I:1450639:03B02:E09 16 13 1480159 I:1480159:06B02:E03 17 14 1509602 I:1509602:04A01:A11 18 15 1516301 I:1516301:05B01:C10 19 167 1598.C19.gz43_212821 M00055583C:B07 20 16 1600586 I:1600586:05B02:F04 21 17 1609538 I:1609538:06A02:F04 22 18 1613615 I:1613615:03B01:D10 23 19 1630804 I:1630804:06A02:F10 24 20 1633286 I:1633286:06A02:E04 25 21 1666080 I:1666080:07B02:D04 26 22 1699587 I:1699587:06A02:F11 27 23 1702266 I:1702266:02B01:D09 28 24 1712592 I:1712592:04A01:E03 29 25 1723834 I:1723834:01A01:C02 30 26 1743234 I:1743234:16B01:D09 31 170 1744.K05.gz43_221934 M00056250C:B02 32 27 1749417 I:1749417:04A02:D10 33 28 1749883 I:1749883:05B01:D04 34 29 1750782 I:1750782:02A01:A08 35 30 1758241 I:1758241:15B02:G04 36 31 1809385 I:1809385:02A02:G04 37 32 1810640 I:1810640:01A02:D06 38 33 1817434 I:1817434:02B01:C02 39 34 1833191 I:1833191:14A01:G05 40 35 1854245 I:1854245:02B02:E10 41 36 1854558 I:1854558:03A01:C11 42 37 1857563 I:1857563:05B02:D01 43 38 1920522 I:1920522:15B02:F02 44 39 1920650 I:1920650:16A01:B01 45 41 1923490 I:1923490:18B01:H08 46 42 1923769 I:1923769:16B01:F01 47 43 1926006 I:1926006:15A01:F09 48 44 1931371 I:1931371:02B02:D12 49 45 1960722 I:1960722:13B02:D11 50 46 1963753 I:1963753:18B01:E07 51 47 1965257 I:1965257:18B02:B04 52 48 1967543 I:1967543:16B02:F06 53 49 1968921 I:1968921:15A02:D06 54 50 1969044 I:1969044:18B01:E12 56 53 1996180 I:1996180:19B01:C11 57 54 2054678 I:2054678:19A01:F10 58 55 2055926 I:2055926:14A01:F11 59 56 2056395 I:2056395:13A02:B07 60 58 2060725 I:2060725:13A01:G10 61 59 2079906 I:2079906:01A02:A06 62 60 2152363 I:2152363:04A02:A08 63 63 2239819 I:2239819:04A02:B11 64 64 2359588 I:2359588:18A01:F03 65 65 2458926 I:2458926:03B01:C07 66 66 2483109 I:2483109:05A01:A06 67 67 2499479 I:2499479:05A01:D06 68 68 2499976 I:2499976:01B02:E09 70 71 2615513 I:2615513:04B01:D09 71 74 2675481 I:2675481:05A01:G06 73 100 268.H2.sp6_144757 M00001341B:A11 74 105 270.B6.sp6_145073 M00001402B:C12 75 106 270.C6.sp6_145085 M00001402C:B01 76 104 270.H3.sp6_145142 M00001393D:F01 77 75 2759046 I:2759046:19B02:C05 78 76 2825369 I:2825369:07A02:F09 79 77 2840195 I:2840195:01B02:G11 80 78 2902903 I:2902903:12A02:F02 81 79 2914605 I:2914605:04B01:G06 82 80 2914719 I:2914719:04B02:B05 83 81 3229778 I:3229778:02B01:B07 84 109 323.B1.sp6_145452 M00001489B:G04 85 110 323.C3.sp6_145466 M00001496A:G03 86 111 324.H1.sp6_145716 M00001558C:B06 87 121 325.H11.sp6_145918 M00005360A:A07 88 118 325.H4.sp6_145911 M00004031B:D12 89 41 344.B2.sp6_146237 M00022742A:F08 90 139 344.C4.sp6_146251 M00023363C:A04 91 83 3518380 I:3518380:16A01:B07 92 85 4072558 I:4072558:12B01:A07 93 117 414.A11.sp6_149879 M00003961B:H05 94 113 414.F2.sp6_149930 M00001675B:G05 95 87 549299 I:549299:17B02:F06 96 88 605019 I:605019:13B02:D03 97 89 620494 I:620494:16A01:C10 98 125 626.D8.sp6_157447 M00007965C:G08 99 128 627.E8.sp6_157651 M00007987D:D04 100 127 627.G6.sp6_157673 M00007985B:A03 101 129 628.D12.sp6_157835 M00008049B:A12 102 130 634.H4.sp6_155966 M00008099D:A05 104 136 642.C6.sp6_156292 M00022168B:F02 106 5 642.D8.sp6_156306 M00022180D:E11 107 137 642.H11.sp6_156357 M00022215C:A10 108 138 653.A3.sp6_158944 M00023283C:C06 109 141 655.B4.sp6_156470 M00023431B:A01 110 90 659143 I:659143:16B01:E06 111 145 661.B5.sp6_159726 M00027066B:E09 112 91 750899 I:750899:16A01:D04 113 92 763607 I:763607:16A01:E09 114 93 901317 I:901317:16A01:G01 116 100 919.H2.SP6_168750 M00001341B:A11 118 123 956.B04.sp6_177996 M00006883D:H12 119 94 956077 I:956077:14B01:H04 120 95 970933 I:970933:14B01:D03 121 96 986558 I:986558:18A01:C09 122 98 998612 I:998612:14B02:G06 123 103 A061.ga43_378496 M00001374A:A06 124 103 A062.ga43_378497 M00001374A:A06 125 133 A121.ga43_378498 M00022009A:A12 126 133 A122.ga43_378499 M00022009A:A12 130 115 G022a.ga43_378503 M00003852B:C01 131 106 RTA00000179AF.k.22.1.Seq M00001402C:B01 132 113 RTA00000187AF.g.2.1.Seq M00001675B:G05 133 113 RTA00000187AR.g.2.2.Seq M00001675B:G05 134 106 RTA00000348R.j.10.1.Seq M00001402C:B01 135 116 RTA00000588F.l.02.2.Seq M00003853B:G11 136 117 RTA00000588F.o.23.1.Seq M00003961B:H05 138 123 RTA00000603F.d.06.1.Seq M00006883D:H12 140 140 RTA00000847F.n.19.3.Seq M00023371A:G03 141 143 RTA00000922F.g.12.1.Seq M00026900D:F02 142 121 RTA00001042F.o.18.1.Seq M00005360A:A07 143 121 RTA00001064F.c.16.1.Seq M00005360A:A07 144 139 RTA00001069F.c.03.1.Seq M00023363C:A04 145 112 RTA00002890F.d.16.1.P.Seq M00001600C:B11 147 166 RTA22200002F.b.15.1.P.Seq M00055435B:A12 148 167 RTA22200003F.b.13.1.P.Seq M00055583C:B07 149 169 RTA22200005F.d.14.1.P.Seq M00055873C:B06 150 30 RTA22200007F.j.17.2.P.Seq M00056227B:G06 151 170 RTA22200007F.m.02.1.P.Sequence M00056250C:B02 152 171 RTA22200008F.a.24.1.P.Seq M00056301D:A04 153 171 RTA22200008F.b.01.1.P.Seq M00056301D:A04 154 172 RTA22200008F.b.22.1.P.Sequence M00056308A:F02 155 147 RTA22200009F.b.03.2.P.Sequence M00042439D:C11 156 149 RTA22200009F.c.22.2.P.Seq M00042756A:H02 157 150 RTA22200009F.e.10.1.P.Seq M00042770D:G04 158 151 RTA22200009F.i.17.2.P.Seq M00042818A:D05 159 173 RTA22200009F.p.21.1.P.Seq M00056350B:B03 161 175 RTA22200010F.k.02.1.P.Seq M00056478D:B07 162 176 RTA22200010F.k.19.1.P.Seq M00056483D:G07 163 177 RTA22200010F.m.13.1.P.Seq M00056500C:A07 164 178 RTA22200011F.b.05.1.P.Seq M00056533D:G07 165 179 RTA22200011F.b.09.1.P.Seq M00056534C:E08 166 180 RTA22200011F.g.21.1.P.Seq M00056585B:F04 168 182 RTA22200011F.l.06.1.P.Seq M00056619A:H02 169 183 RTA22200011F.l.15.1.P.Seq M00056622B:F12 170 184 RTA22200011F.m.13.1.P.Seq M00056632B:H10 171 185 RTA22200011F.n.24.1.P.Seq M00056645C:D11 172 185 RTA22200011F.o.01.1.P.Seq M00056645C:D11 173 186 RTA22200011F.o.03.1.P.Seq M00056646B:F07 174 187 RTA22200012F.c.01.1.P.Seq M00056679B:H03 176 189 RTA22200012F.f.15.1.P.Seq M00056709B:D03 177 190 RTA22200012F.i.14.1.P.Seq M00056728C:G02 179 192 RTA22200013F.b.20.1.P.Seq M00056810A:A02 180 193 RTA22200013F.c.06.1.P.Seq M00056812D:A08 181 194 RTA22200013F.d.15.1.P.Seq M00056822A:E08 182 195 RTA22200013F.o.17.1.P.Seq M00056908A:H05 183 196 RTA22200013F.p.24.1.P.Seq M00056918C:F09 184 197 RTA22200014F.b.18.1.P.Seq M00056937C:C10 185 197 RTA22200014F.b.18.2.P.Seq M00056937C:C10 190 199 RTA22200014F.j.08.1.P.Seq M00056992C:F12 191 199 RTA22200014F.j.08.2.P.Seq M00056992C:F12 192 200 RTA22200015F.a.18.1.P.Seq M00057044D:G03 193 176 RTA22200015F.a.23.1.P.Seq M00057046A:G09 194 201 RTA22200015F.f.17.1.P.Seq M00057081B:H03 196 118 RTA22200015F.k.10.1.P.Seq M00057112B:E11 198 204 RTA22200015F.m.15.1.P.Seq M00057127B:B09 200 206 RTA22200016F.i.21.1.P.Seq M00057231A:G04 201 207 RTA22200016F.k.08.1.P.Seq M00057241C:F03 202 152 RTA22200019F.h.04.1.P.Seq M00054500D:C08 204 151 RTA22200019F.j.24.1.P.Seq M00054520A:D04 205 151 RTA22200019F.k.01.1.P.Seq M00054520A:D04 206 153 RTA22200019F.m.05.1.P.Seq M00054538C:C01 207 154 RTA22200020F.i.12.1.P.Seq M00054639D:F05 208 155 RTA22200020F.j.09.1.P.Seq M00054647A:A09 209 156 RTA22200020F.j.24.1.P.Seq M00054650D:E04 210 157 RTA22200021F.d.09.2.P.Seq M00054742C:B12 211 158 RTA22200021F.g.18.3.P.Seq M00054769A:E05 212 159 RTA22200021F.h.15.3.P.Seq M00054777D:E09 213 160 RTA22200021F.i.23.3.P.Seq M00054806B:G03 214 161 RTA22200022F.d.04.1.P.Seq M00054893C:D03 215 162 RTA22200022F.m.09.1.P.Seq M00054971D:D07 217 195 RTA22200024F.i.11.1.P.Seq M00055209C:B07 218 164 RTA22200024F.p.03.1.P.Seq M00055258B:D12 220 65 RTA22200026F.d.17.1.P.Seq M00055423A:C07 222 124 RTA22200231F.b.20.1.P.Seq M00007935D:A05 223 126 RTA22200231F.l.22.1.P.Seq M00007985A:B08 224 132 RTA22200232F.d.23.1.P.Seq M00021956B:A09 225 291 RTA22200232F.m.17.1.P.Seq M00022140A:E11 226 142 RTA22200241F.e.15.1.P.Seq M00026888A:A03 227 144 RTA22200241F.g.22.1.P.Seq M00026903D:D11 228 115 X2.ga43_378506 M00003852B:C01 230 255 gb|AA024920.1|AA024920 RG:364972:10009:B06 231 262 gb|AA033519.1|AA033519 RG:471154:10009:H04 232 256 gb|AA039790.1|AA039790 RG:376554:10009:B12 233 263 gb|AA043829.1|AA043829 RG:487171:10009:H09 234 265 gb|AA070046.1|AA070046 RG:530002:10002:A08 235 264 gb|AA128438.1|AA128438 RG:526536:10002:A02 236 266 gb|AA179757.1|AA179757 RG:612874:10002:G02 239 269 gb|AA232253.1|AA232253 RG:666323:10010:B07 240 270 gb|AA234451.1|AA234451 RG:669110:10010:B12 242 273 gb|AA399596.1|AA399596 RG:729913:10010:G11 243 276 gb|AA400338.1|AA400338 RG:742764:10011:A06 247 236 gb|AA431134.1|AA431134 RG:781507:10011:E01 248 277 gb|AA446295.1|AA446295 RG:781028:10011:D08 249 278 gb|AA448898.1|AA448898 RG:785368:10011:E11 250 278 gb|AA449542.1|AA449542 RG:785846:10011:F02 252 274 gb|AA477696.1|AA477696 RG:740831:10010:H12 253 280 gb|AA530983.1|AA530983 RG:985973:10012:B09 254 259 gb|AA679027.1|AA679027 RG:432960:10009:E11 255 210 gb|AA723679.1|AA723679 RG:1325847:10012:H07 256 213 gb|AA829074.1|AA829074 RG:1374447:20004:G01 257 212 gb|AA830348.1|AA830348 RG:1353123:10013:A06 258 214 gb|AA885302.1|AA885302 RG:1461567:10013:E03 260 216 gb|AA926951.1|AA926951 RG:1552386:10013:G04 262 219 gb|AI004332.1|AI004332 RG:1631867:10014:B06 263 252 gb|AI015644.1|AI015644 RG:1635546:10014:B08 264 220 gb|AI017336.1|AI017336 RG:1638979:10014:C04 265 218 gb|AI018495.1|AI018495 RG:1630930:10014:B05 266 221 gb|AI031810.1|AI031810 RG:1645945:10014:D05 267 226 gb|AI054129.1|AI054129 RG:1861510:20001:B03 268 212 gb|AI066521.1|AI066521 RG:1637619:10014:C02 269 223 gb|AI076187.1|AI076187 RG:1674098:10014:H01 270 221 gb|AI079570.1|AI079570 RG:1674393:10014:H02 271 206 gb|AI123832.1|AI123832 RG:1651303:10014:E01 272 225 gb|AI207972.1|AI207972 RG:1838677:10015:E10 273 231 gb|AI224731.1|AI224731 RG:2002384:20003:E01 274 233 gb|AI265824.1|AI265824 RG:2006592:20003:F12 275 232 gb|AI279390.1|AI279390 RG:2006302:20003:F08 276 227 gb|AI298668.1|AI298668 RG:1895716:10015:G09 277 229 gb|AI305997.1|AI305997 RG:1996788:20003:C10 278 230 gb|AI306323.1|AI306323 RG:1996901:20003:D01 279 239 gb|AI335279.1|AI335279 RG:2055807:10016:B09 280 238 gb|AI336511.1|AI336511 RG:2051667:20003:H05 281 228 gb|AI347995.1|AI347995 RG:1927470:10015:H08 282 235 gb|AI356632.1|AI356632 RG:2012168:10016:B05 283 237 gb|AI375104.1|AI375104 RG:2048081:10016:B08 284 241 gb|AI421409.1|AI421409 RG:2097257:10016:C07 285 242 gb|AI421521.1|AI421521 RG:2097294:10016:C08 286 243 gb|AI523571.1|AI523571 RG:2117694:10016:E01 287 258 gb|H00135.1|H00135 RG:43296:10005:C03 288 261 gb|H08424.1|H08424 RG:45623:10005:D09 289 260 gb|H12948.1|H12948 RG:43534:10005:C04 290 236 gb|H54104.1|H54104 RG:203031:10007:A09 293 246 gb|N55598.1|N55598 RG:244601:10007:E02 294 245 gb|N75655.1|N75655 RG:244132:10007:E01 295 248 gb|N98702.1|N98702 RG:278409:10008:B10 296 129 gb|R12138.1|R12138 RG:25258:10004:D09 298 2 gb|R17980.1|R17980 RG:32281:10004:G05 299 254 gb|R21293.1|R21293 RG:35892:10004:H10 300 249 gb|R41558.1|R41558 RG:29739:10004:F02 301 2 gb|R56713.1|R56713 RG:41097:10005:B10 302 224 gb|R85309.1|R85309 RG:180296:10006:G03 303 222 gb|R87679.1|R87679 RG:166410:10006:F01 304 208 gb|T83145.1|T83145 RG:110764:10005:H04 305 250 gb|W16960.1|W16960 RG:301608:10008:D09 306 251 gb|W24201.1|W24201 RG:306813:10008:E12 307 252 gb|W45587.1|W45587 RG:323425:10008:F11 308 253 gb|W69496.1|W69496 RG:343821:10008:H05 309 257 gb|W87460.1|W87460 RG:417109:10009:D09

Summary of Blast Search Results

Table 3 (inserted before the claims) provides the results of BLASTN searches of the Cenbank database using the sequences of the polynucleotides as described above. Table 3 includes 1) the SEQ ID NO; 2) the “CID” or Candidate Identification Number to which the sequence is assigned; 3) the GenBank accession number of the Blast hit; 4) a description of the gene encoded by the Blast hit (“HitDesc”) having the closest sequence homology to the sequence on the array (and in some instances contains a sequence identical to the sequence on the array); 5) the Blast score (“Score”), which value is obtained by adding the similarities and differences of an alignment between the sequence and the database sequence, wherein a “match” is a positive value and a “mismatch” or “no-match” is a negative value; 6) the “Length” of the sequence, which represents the number of nucleotides in the database “hit”; 7) the Expect value (E) which describes the number of hits or matches “expected” if the database was random sequence, i.e. the E value describes the random background noise that exists for matches between sequences; and 8) the “Identities” ratio which is a ratio of number of bases in the query sequence that exactly match the number of bases in the database sequence when aligned. TABLE 3 SEQ GenBank ID Accession NO CID No. HitDesc Score Length Expect Identities 1 114 D29958 gi|473948|dbj|D29958.1|HUMORFA10 573 1011 1E−162 289/289 Human mRNA for KIAA0116 gene, partial cds 2 123 NM_020510 gi|10048405|ref|NM_020510.1| Mus 77.8 2112 3E−12 39/39 musculus frizzled homolog 10 (Drosophila) (Fzd10), mRNA 3 114 D29958 gi|473948|dbj|D29958.1|HUMORFA10 969 1011 0 559/575 Human mRNA for KIAA0116 gene, partial cds 4 1 XM_001344 gi|11421753|ref|XM_001344.1| Homo 464 512 1E−129 234/234 sapiens S100 calcium-binding protein A4 (calcium protein, calvasculin, metastasin, murine placental homolog) (S100A4), mRNA 5 2 NM_004443 gi|4758287|ref|NM_004443.1| Homo 194 3805 3E−48 137/145 sapiens EphB3 (EPHB3) mRNA 6 3 BC001014 gi|12654380|gb|BC001014.1|BC001014 444 1378 1E−123 224/224 Homo sapiens, Similar to methylenetetrahydrofolate dehydrogenase (NADP+ dependent), methenyltetrahydrofolate cyclohydrolase, formyltetrahydrofolate synthetase, clone IMAGE: 3344724, mRNA, partial cds 7 4 NM_001363 gi|4503336|ref|NM_001363.1| Homo 513 2422 1E−144 259/259 sapiens dyskeratosis congenita 1, dyskerin (DKC1), mRNA 8 5 NM_001699 gi|11863124|ref|NM_001699.2| Homo 543 4986 1E−153 281/282 sapiens AXL receptor tyrosine kinase (AXL), transcript variant 2, mRNA 9 6 NM_001827 gi|4502858|ref|NM_001827.1| Homo 535 627 1E−150 279/282 sapiens CDC28 protein kinase 2 (CKS2), mRNA 10 7 XM_011126 gi|12730374|ref|XM_011126.1| Homo 515 2219 1E−144 260/260 sapiens Arg/Abl-interacting protein ArgBP2 (ARGBP2), mRNA 11 8 BC002718 gi|12803760|gb|BC002718.1|BC002718 299 1028 1E−79 223/236 Homo sapiens, type I transmembrane protein Fn14, clone MGC: 3386, mRNA, complete cds 12 9 XM_007891 gi|11430799|ref|XM_007891.1| Homo 317 3171 3E−85 160/160 sapiens cadherin 3, type 1, P-cadherin (placental) (CDH3), mRNA 13 10 BC001883 gi|12804870|gb|BC001883.1|BC001883 490 2464 1E−137 255/259 Homo sapiens, nucleolar phosphoprotein p130, clone MGC: 1494, mRNA, complete cds 14 11 XM_002532 gi|11429973|ref|XM_002532.1| Homo 440 1132 1E−122 244/255 sapiens 26S proteasome-associated pad1 homolog (POH1), mRNA 15 12 BC005334 gi|13529121|gb|BC005334.1|BC005334 494 1047 1E−138 258/260 Homo sapiens, centrin, EF-hand protein, 2, clone MGC: 12421, mRNA, complete cds 16 13 XM_009001 gi|12742166|ref|XM_009001.2| Homo 462 1506 1E−128 233/233 sapiens kallikrein 6 (neurosin, zyme) (KLK6), mRNA 17 14 XM_005818 gi|12735488|ref|XM_005818.2| Homo 373 2420 1E−102 188/188 sapiens arachidonate 5-lipoxygenase (ALOX5), mRNA 18 15 XM_012273 gi|12737900|ref|XM_012273.1| Homo 396 3314 1E−109 200/200 sapiens forkhead box M1 (FOXM1), mRNA 19 167 AK000140 gi|7020034|dbj|AK000140.1|AK000140 1114 1403 0 587/596 Homo sapiens cDNA FLJ20133 fis, clone COL06539 20 16 BC003146 gi|13111946|gb|BC003146.1|BC003146 432 1720 1E−119 218/218 Homo sapiens, splicing factor 3b, subunit 3, 130 kD, clone MGC: 3924, mRNA, complete cds 21 17 BC001763 gi|12804676|gb|BC001763.1|BC001763 404 1917 1E−111 206/207 Homo sapiens, Similar to translocase of outer mitochondrial membrane 34, clone MGC: 1252, mRNA, complete cds 22 18 XM_007326 gi|11434291|ref|XM_007326.1| Homo 404 1944 1E−111 204/204 sapiens bone morphogenetic protein 4 (BMP4), mRNA 23 19 XM_005376 gi|12734932|ref|XM_005376.2| Homo 371 1503 1E−101 192/194 sapiens Friedreich ataxia (FRDA), mRNA 24 20 XM_010945 gi|12729201|ref|XM_010945.1| Homo 452 614 1E−125 228/228 sapiens hypothetical gene supported by XM_010945 (LOC65371), mRNA 25 21 AK018953 gi|12858931|dbj|AK018953.1|AK018953 174 1297 5E−42 174/203 Mus musculus adult male testis cDNA, RIKEN full-length enriched library, clone: 1700111D04, full insert sequence 26 22 BC003635 gi|13177711|gb|BC003635.1|BC003635 456 1140 1E−127 230/230 Homo sapiens, matrix metalloproteinase 7 (matrilysin, uterine), clone MGC: 3913, mRNA, complete cds 27 23 XM_008589 gi|11427373|ref|XM_008589.1| Homo 440 1790 1E−122 224/225 sapiens pyrroline-5-carboxylate reductase 1 (PYCR1), mRNA 28 24 BC001880 gi|12804864|gb|BC001880.1|BC001880 379 1469 1E−103 191/191 Homo sapiens, Similar to insulin induced gene 1, clone MGC: 1405, mRNA, complete cds 29 25 XM_003047 gi|12729625|ref|XM_003047.2| Homo 353 3383 7E−96 178/178 sapiens minichromosome maintenance deficient (S. cerevisiae) 2 (mitotin) (MCM2), mRNA 30 26 NC_002548 gi|10314009|ref|NC_002548.1| Acute bee 38.2 9491 0.68 19/19 paralysis virus, complete genome 31 170 NM_004219 gi|11038651|ref|NM_004219.2| Homo 1314 728 0 667/669 sapiens pituitary tumor-transforming 1 (PTTG1), mRNA 32 27 BC002479 gi|12803322|gb|BC002479.1|BC002479 613 1479 1E−174 309/309 Homo sapiens, cathepsin H, clone MGC: 1519, mRNA, complete cds 33 28 BC000123 gi|12652744|gb|BC000123.1|BC000123 545 1331 1E−153 275/275 Homo sapiens, pyridoxal (pyridoxine, vitamin B6) kinase, clone MGC: 3128, mRNA, complete cds 34 29 AK000836 gi|7021154|dbj|AK000836.1|AK000836 406 1703 1E−112 205/205 Homo sapiens cDNA FLJ20829 fis, clone ADKA03163, highly similar to D26488 Human mRNA for KIAA0007 gene 35 30 BC001425 gi|12655140|gb|BC001425.1|BC001425 504 2499 1E−141 256/257 Homo sapiens, Similar to differential display and activated by p53, clone MGC: 1780, mRNA, complete cds 36 31 BC005301 gi|13529028|gb|BC005301.1|BC005301 442 998 1E−122 225/226 Homo sapiens, integrin beta 3 binding protein (beta3-endonexin), clone MGC: 12370, mRNA, complete cds 37 32 Z27409 gi|482916|emb|Z27409.1|HSRTKEPH 529 2398 1E−149 276/278 H. sapiens mRNA for receptor tyrosine kinase eph (partial) 38 33 XM_003107 gi|12729732|ref|XM_003107.2| Homo 436 1985 1E−120 227/228 sapiens transketolase (Wernicke- Korsakoff syndrome) (TKT), mRNA 39 34 AB002297 gi|2224538|dbj|AB002297.1|AB002297 387 8063 1E−106 208/211 Human mRNA for KIAA0299 gene, partial cds 40 35 XM_002591 gi|12728749|ref|XM_002591.2| Homo 502 4732 1E−140 253/253 sapiens KIAA0173 gene product (KIAA0173), mRNA 41 36 XM_009101 gi|11425196|ref|XM_009101.1| Homo 523 3374 1E−147 271/272 sapiens fucosyltransferase 1 (galactoside 2-alpha-L-fucosyltransferase, Bombay phenotype included) (FUT1), mRNA 42 37 AF082858 gi|4587463|gb|AF082858.1|AF082858 494 829 1E−138 249/249 Homo sapiens pterin carbinolamine dehydratase (PCD) mRNA, complete cds 43 38 BC001600 gi|12804396|gb|BC001600.1|BC001600 533 1316 1E−150 269/269 Homo sapiens, D123 gene product, clone MGC: 1935, mRNA, complete cds 44 39 BC000871 gi|12654114|gb|BC000871.1|BC000871 609 1489 1E−172 307/307 Homo sapiens, annexin A3, clone MGC: 5043, mRNA, complete cds 45 41 AL136600 gi|13276700|emb|AL136600.1|HSM8015 504 1552 1E−141 254/254 74 Homo sapiens mRNA; cDNA DKFZp564I1216 (from clone DKFZp564I1216); complete cds 46 42 AK024772 gi|10437149|dbj|AK024772.1|AK024772 484 864 1E−135 246/247 Homo sapiens cDNA: FLJ21119 fis, clone CAS05644, highly similar to HSA272196 Homo sapiens mRNA for hypothetical protein 47 43 BC004246 gi|13279007|gb|BC004246.1|BC004246 438 4249 1E−121 221/221 Homo sapiens, mutS (E. coli) homolog 6, clone MGC: 10498, mRNA, complete cds 48 44 X92474 gi|1045056|emb|X92474.1|HSCHTOG 238 6449 2E−61 122/123 H. sapiens mRNA for ch-TOG protein 49 45 BC002994 gi|12804270|gb|BC002994.1|BC002994 476 2238 1E−132 246/248 Homo sapiens, clone MGC: 3823, mRNA, complete cds 50 46 AK025062 gi|10437501|dbj|AK025062.1|AK025062 327 2692 4E−88 174/176 Homo sapiens cDNA: FLJ21409 fis, clone COL03924 51 47 AP001247 gi|10121151|dbj|AP001247.3|AP001247 36.2 16950 2.8 20/21 Homo sapiens genomic DNA, chromosome 2p11.2, clone: lambda316 52 48 AF131838 gi|4406677|gb|AF131838.1|AF131838 498 1462 1E−139 251/251 Homo sapiens clone 25107 mRNA sequence 53 49 XM_007647 gi|11432476|ref|XM_007647.1| Homo 531 2111 1E−149 268/268 sapiens immunoglobulin superfamily containing leucine-rich repeat (ISLR), mRNA 54 50 AB048286 gi|13537296|dbj|AB048286.1|AB048286 476 2713 1E−132 247/248 Homo sapiens GS1999full mRNA, complete cds 56 53 AK001515 gi|7022818|dbj|AK001515.1|AK001515 333 884 6E−90 168/168 Homo sapiens cDNA FLJ10653 fis, clone NT2RP2005890 57 54 AB023156 gi|4589521|dbj|AB023156.1|AB023156 42.1 5537 0.055 24/25 Homo sapiens mRNA for KIAA0939 protein, partial cds 58 55 XM_008622 gi|12740774|ref|XM_008622.2| Homo 507 1427 1E−142 256/256 sapiens thymidine kinase 1, soluble (TK1), mRNA 59 56 XM_003758 gi|11416585|ref|XM_003758.1| Homo 422 2691 1E−116 215/216 sapiens transforming growth factor, beta- induced, 68 kD (TGFBI), mRNA 60 58 XM_001732 gi|11423748|ref|XM_001732.1| Homo 500 2435 1E−140 252/252 sapiens calcyclin binding protein (CACYBP), mRNA 61 59 BC001866 gi|12804840|gb|BC001866.1|BC001866 396 2097 1E−109 239/256 Homo sapiens, replication factor C (activator 1) 5 (36.5 kD), clone MGC: 1155, mRNA, complete cds 62 60 BC000293 gi|12653056|gb|BC000293.1|BC000293 87.7 733 2E−16 58/65 Homo sapiens, non-metastatic cells 1, protein (NM23A) expressed in, clone MGC: 8334, mRNA, complete cds 63 63 XM_008043 gi|12739769|ref|XM_008043.2| Homo 519 1739 1E−146 262/262 sapiens dipeptidase 1 (renal) (DPEP1), mRNA 64 64 AB052751 gi|11967903|dbj|AB052751.1|AB052751 527 1863 1E−148 266/266 Homo sapiens Axin2 mRNA for conductin, partial cds and 3′UTR 65 65 BC005832 gi|13543336|gb|BC005832.1|BC005832 460 1444 1E−128 232/232 Homo sapiens, KIAA0101 gene product, clone MGC: 2250, mRNA, complete cds 66 66 XM_002190 gi|11428365|ref|XM_002190.1| Homo 472 3152 1E−131 238/238 sapiens chromosome 1 open reading frame 2 (C1ORF2), mRNA 67 67 XM_010360 gi|12743462|ref|XM_010360.2| Homo 505 3746 1E−141 255/255 sapiens transcription factor NRF (NRF), mRNA 68 68 AL122064 gi|6102857|emb|AL122064.1|HSM801208 502 1320 1E−140 257/259 Homo sapiens mRNA; cDNA DKFZp434M231 (from clone DKFZp434M231); partial cds 70 71 XM_005226 gi|11425871|ref|XM_005226.1| Homo 507 2619 1E−142 256/256 sapiens antizyme inhibitor (LOC51582), mRNA 71 74 BC002956 gi|12804196|gb|BC002956.1|BC002956 484 1185 1E−135 244/244 Homo sapiens, ClpP (caseinolytic protease, ATP-dependent, proteolytic subunit, E. coli) homolog, clone MGC: 1379, mRNA, complete cds 73 100 NM_014791 gi|7661973|ref|NM_014791.1| Homo 1211 2470 0 691/708 sapiens KIAA0175 gene product (KIAA0175), mRNA 74 105 BC005864 gi|13543414|gb|BC005864.1|BC005864 1108 1430 0 621/635 Homo sapiens, cyclin-dependent kinase 4, clone MGC: 3719, mRNA, complete cds 75 106 XM_005404 gi|11428250|ref|XM_005404.1| Homo 1203 2446 0 631/638 sapiens catenin (cadherin-associated protein), alpha-like 1 (CTNNAL1), mRNA 76 104 BC002362 gi|12803116|gb|BC002362.1|BC002362 1269 1318 0 643/644 Homo sapiens, lactate dehydrogenase B, clone MGC: 8627, mRNA, complete cds 77 75 AF065389 gi|3152702|gb|AF065389.1|AF065389 434 1405 1E−120 236/244 Homo sapiens tetraspan NET-4 mRNA, complete cds 78 76 BC004863 gi|13436073|gb|BC004863.1|BC004863 587 2229 1E−166 303/304 Homo sapiens, Similar to phosphoserine aminotransferase, clone MGC: 10519, mRNA, complete cds 79 77 XM_011917 gi|12735709|ref|XM_011917.1| Homo 509 1414 1E−143 259/260 sapiens adenosine kinase (ADK), mRNA 80 78 BC000897 gi|12654158|gb|BC000897.1|BC000897 143 683 8E−33 102/107 Homo sapiens, interferon induced transmembrane protein 1 (9-27), clone MGC: 5195, mRNA, complete cds 81 79 NM_014641 gi|7661965|ref|NM_014641.1| Homo 335 6940 3E−90 196/206 sapiens KIAA0170 gene product (KIAA0170), mRNA 82 80 XM_012967 gi|12742527|ref|XM_012967.1| Homo 430 1188 1E−119 231/233 sapiens RAE1 (RNA export 1, S. pombe) homolog (RAE1), mRNA 83 81 XM_003913 gi|12719136|ref|XM_003913.2| Homo 571 5348 1E−161 288/288 sapiens integrin, alpha 2 (CD49B, alpha 2 subunit of VLA-2 receptor) (ITGA2), mRNA 84 109 AK024039 gi|10436304|dbj|AK024039.1|AK024039 422 2224 1E−116 377/443 Homo sapiens cDNA FLJ13977 fis, clone Y79AA1001603, weakly similar to POLYPEPTIDE N- ACETYLGALACTOSAMINYLTRANSFERASE (EC 2.4.1.41) 85 110 XM_009492 gi|11420665|ref|XM_009492.1| Homo 852 2627 0 440/444 sapiens v-myb avian myeloblastosis viral oncogene homolog-like 2 (MYBL2), mRNA 86 111 XM_009587 gi|12742401|ref|XM_009587.2| Homo 749 2108 0 392/394 sapiens TH1 drosophila homolog (HSPC130), mRNA 87 121 NM_001408 gi|13325063|ref|NM_001408.1| Homo 1067 10531 0 627/660 sapiens cadherin, EGF LAG seven-pass G-type receptor 2, flamingo (Drosophila) homolog (CELSR2), mRNA 88 118 AF226998 gi|12655885|gb|AF226998.1|AF226998 775 734 0 391/391 Homo sapiens dpy-30-like protein mRNA, complete cds 89 41 BC001106 gi|12654544|gb|BC001106.1|BC001106 416 1542 1E−114 214/216 Homo sapiens, hypothetical protein, clone MGC: 891, mRNA, complete cds 90 139 XM_009005 gi|11424670|ref|XM_009005.1| Homo 1112 1186 0 617/630 sapiens kallikrein 11 (KLK11), mRNA 91 83 XM_006067 gi|12736004|ref|XM_006067.2| Homo 321 2525 4E−86 189/194 sapiens 7-dehydrocholesterol reductase (DHCR7), mRNA 92 85 AF092569 gi|3986473|gb|AF092569.1|HSEIFP1 87.7 299 2E−16 74/79 Homo sapiens translation initiation factor eIF3 p40 subunit gene, exon 1 93 117 BC004264 gi|13279061|gb|BC004264.1|BC004264 1021 3138 0 564/582 Homo sapiens, Similar to EphB4, clone IMAGE: 3611312, mRNA, partial cds 94 113 BC000277 gi|12802987|gb|BC000277.1|BC000277 1011 2947 0 586/618 Homo sapiens, clone MGC: 1892, mRNA, complete cds 95 87 NM_015339 gi|12229216|ref|NM_015339.1| Homo 599 4713 1E−169 302/302 sapiens activity-dependent neuroproctective protein (ADNP), mRNA 96 88 XM_009845 gi|11526339|ref|XM_009845.1| Homo 505 1291 1E−141 255/255 sapiens catechol-O-methyltransferase (COMT), mRNA 97 89 BC000509 gi|12653474|gb|BC000509.1|BC000509 517 1008 1E−145 261/261 Homo sapiens, proteasome (prosome, macropain) subunit, beta type, 7, clone MGC: 8507, mRNA, complete cds 98 125 AK024618 gi|10436934|dbj|AK024618.1|AK024618 1199 1804 0 662/676 Homo sapiens cDNA: FLJ20965 fis, clone ADSH01104 99 128 D80001 gi|1136417|dbj|D80001.1|D80001 1138 4994 0 639/663 Human mRNA for KIAA0179 gene, partial cds 100 127 BC004899 gi|13436169|gb|BC004899.1|BC004899 930 1688 0 579/619 Homo sapiens, sigma receptor (SR31747 binding protein 1), clone MGC: 3851, mRNA, complete cds 101 129 BC003129 gi|13111916|gb|BC003129.1|BC003129 1043 1882 0 583/602 Homo sapiens, non-POU-domain- containing, octamer-binding, clone MGC: 3380, mRNA, complete cds 102 130 XM_009690 gi|12742251|ref|XM_009690.2| Homo 438 2277 1E−121 367/404 sapiens hypothetical protein FLJ10850 (FLJ10850), mRNA 104 136 XM_005908 gi|11432093|ref|XM_005908.1| Homo 1235 2237 0 642/646 sapiens hypothetical protein FLJ10540 (FLJ10540), mRNA 106 5 NM_001699 gi|11863124|ref|NM_001699.2| Homo 922 4986 0 550/572 sapiens AXL receptor tyrosine kinase (AXL), transcript variant 2, mRNA 107 137 NM_025927 gi|13385417|ref|NM_025927.1| Mus 228 1486 1E−57 223/259 musculus RIKEN cDNA 2600005P05 gene (2600005P05Rik), mRNA 108 138 AK023154 gi|10434948|dbj|AK023154.1|AK023154 924 3040 0 524/541 Homo sapiens cDNA FLJ13092 fis, clone NT2RP3002147 109 141 AB017710 gi|5821114|dbj|AB017710.1|AB017710 1067 2353 0 570/582 Homo sapiens U50HG genes for U50′ snoRNA and U50 snoRNA, complete sequence 110 90 NM_011775 gi|6756080|ref|NM_011775.1| Mus 40.1 2185 0.21 20/20 musculus zona pellucida glycoprotein 2 (Zp2), mRNA 111 145 AF086315 gi|3483660|gb|AF086315.1|HUMZD52F10 841 600 0 467/480 Homo sapiens full length insert cDNA clone ZD52F10 112 91 XM_002596 gi|12728741|ref|XM_002596.2| Homo 361 2877 4E−98 201/209 sapiens protein tyrosine phosphatase, receptor type, N (PTPRN), mRNA 113 92 XM_004484 gi|11418942|ref|XM_004484.1| Homo 482 1325 1E−134 243/243 sapiens tumor protein D52-like 1 (TPD52L1), mRNA 114 93 BC000331 gi|12653128|gb|BC000331.1|BC000331 583 935 1E−165 305/310 Homo sapiens, proteasome (prosome, macropain) subunit, beta type, 4, clone MGC: 8522, mRNA, complete cds 116 100 NM_014791 gi|7661973|ref|NM_014791.1| Homo 1185 2470 0 644/664 sapiens KIAA0175 gene product (KIAA0175), mRNA 118 123 XM_004185 gi|12731991|ref|XM_004185.2| Homo 751 4092 0 463/481 sapiens valyl-tRNA synthetase 2 (VARS2), mRNA 119 94 XM_004750 gi|12733059|ref|XM_004750.2| Homo 484 629 1E−135 244/244 sapiens nudix (nucleoside diphosphate linked moiety X)-type motif 1 (NUDT1), mRNA 120 95 XM_006928 gi|12737727|ref|XM_006928.2| Homo 412 4870 1E−113 239/248 sapiens FOXJ2 forkhead factor (LOC55810), mRNA 121 96 AL133104 gi|6453587|emb|AL133104.1|HSM801384 601 1186 1E−170 303/303 Homo sapiens mRNA; cDNA DKFZp434E1822 (from clone DKFZp434E1822); partial cds 122 98 BC004528 gi|1358647|gb|BC004528.1|BC004528 466 2751 1E−129 244/246 Homo sapiens, clone MGC: 3017, mRNA, complete cds 123 103 AF097514 gi|4808600|gb|AF097514.1|AF097514 1302 5221 0 721/738 Homo sapiens stearoyl-CoA desaturase (SCD) mRNA, complete cds 124 103 AF097514 gi|4808600|gb|AF097514.1|AF097514 1328 5221 0 720/734 Homo sapiens stearoyl-CoA desaturase (SCD) mRNA, complete cds 125 133 AF220656 gi|7107358|gb|AF220656.1|AF220656 936 3227 0 529/539 Homo sapiens apoptosis-associated nuclear protein PHLDA1 (PHLDA1) mRNA, partial cds 126 133 AF220656 gi|7107358|gb|AF220656.1|AF220656 969 3227 0 544/555 Homo sapiens apoptosis-associated nuclear protein PHLDA1 (PHLDA1) mRNA, partial cds 130 115 AF019770 gi|2674084|gb|AF019770.1|AF019770 1277 1202 0 735/751 Homo sapiens macrophage inhibitory cytokine-1 (MIC-1) mRNA, complete cds 131 106 AK022926 gi|10434597|dbj|AK022926.1|AK022926 589 2455 1E−166 299/300 Homo sapiens cDNA FLJ12864 fis, clone NT2RP2003604, highly similar to Homo sapiens alpha-catenin-like protein (CTNNAL1) mRNA 132 113 BC000277 gi|12802987|gb|BC000277.1|BC000277 513 2947 1E−144 262/263 Homo sapiens, clone MGC: 1892, mRNA, complete cds 133 113 XM_006213 gi|12736410|ref|XM_006213.2| Homo 579 6477 1E−163 299/300 sapiens KIAA0712 gene product (KIAA0712), mRNA 134 106 XM_005404 gi|11428250|ref|XM_005404.1| Homo 561 2446 1E−158 300/306 sapiens catenin (cadherin-associated protein), alpha-like 1 (CTNNAL1), mRNA 135 116 BC001068 gi|12654476|gb|BC001068.1|BC001068 595 2333 1E−168 300/300 Homo sapiens, clone IMAGE: 2823731, mRNA, partial cds 136 117 BC004264 gi|13279061|gb|BC004264.1|BC004264 486 3138 1E−135 250/252 Homo sapiens, Similar to EphB4, clone IMAGE: 3611312, mRNA, partial cds 138 123 Y09668 gi|1834428|emb|Y09668.1|DRTKLELF1 36.2 2272 3.5 18/18 D. rerio mRNA for tyrosine kinase ligand (elf-1) 140 140 XM_008802 gi|12741169|ref|XM_008802.2| Homo 710 3185 0 358/358 sapiens retinoblastoma-binding protein 8 (RBBP8), mRNA 141 143 XM_009111 gi|12741675|ref|XM_009111.2| Homo 672 1453 0 362/367 sapiens sulfotransferase family, cytosolic, 2B, member 1 (SULT2B1), mRNA 142 121 NM_001408 gi|13325063|ref|NM_001408.1| Homo 755 10531 0 388/389 sapiens cadherin, EGF LAG seven-pass G-type receptor 2, flamingo (Drosophila) homolog (CELSR2), mRNA 143 121 NM_001408 gi|13325063|ref|NM_001408.1| Homo 741 10531 0 376/377 sapiens cadherin, EGF LAG seven-pass G-type receptor 2, flamingo (Drosophila) homolog (CELSR2), mRNA 144 139 XM_009005 gi|11424670|ref|XM_009005.1| Homo 622 1186 1E−176 340/346 sapiens kallikrein 11 (KLK11), mRNA 145 112 XM_003733 gi|12731080|ref|XM_003733.2| Homo 753 2088 0 380/380 sapiens DEAD-box protein abstrakt (ABS), mRNA 147 166 AF216754 gi|6707650|gb|AF216754.1|AF216754 567 354 1E−160 296/298 Homo sapiens over-expressed breast tumor protein (OBTP) mRNA, complete cds 148 167 XM_003384 gi|12730453|ref|XM_003384.2| Homo 640 748 0 323/323 sapiens hypothetical protein (LOC51316), mRNA 149 169 XM_009527 gi|11420875|ref|XM_009527.1| Homo 751 594 0 382/383 sapiens secretory leukocyte protease inhibitor (antileukoproteinase) (SLPI), mRNA 150 30 AF279897 gi|12751120|gb|AF279897.1|AF279897 654 727 0 333/334 Homo sapiens PNAS-143 mRNA, complete cds 151 170 NM_004219 gi|11038651|ref|NM_004219.2| Homo 730 728 0 368/368 sapiens pituitary tumor-transforming 1 (PTTG1), mRNA 152 171 S76771 gi|914225|gb|S76771.1|S76771 210 6849 1E−52 168/185 TPO = thrombopoietin [human, Genomic, 6849 nt] 153 171 M81890 gi|186274|gb|M81890.1|HUMIL11A 216 6870 2E−54 180/203 Human interleukin 11 (IL11) gene, complete mRNA 154 172 XM_004952 gi|12733392|ref|XM_004952.2| Homo 603 2861 1E−171 310/312 sapiens solute carrier family 26, member 3 (SLC26A3), mRNA 155 147 XM_009488 gi|12742285|ref|XM_009488.21| Homo 716 770 0 361/361 sapiens ubiquitin carrier protein E2-C (UBCH10), mRNA 156 149 XM_011755 gi|12734624|ref|XM_011755.1| Homo 733 2566 0 370/370 sapiens SET translocation (myeloid leukemia-associated) (SET), mRNA 157 150 L19183 gi|307154|gb|L19183.1|HUMMAC30X 593 2002 1E−168 323/331 Human MAC30 mRNA, 3′ end 158 151 AK024303 gi|10436651|dbj|AK024303.1|AK024303 698 1591 0 352/352 Homo sapiens cDNA FLJ14241 fis, clone OVARC1000533 159 173 BC001410 gi|12655116|gb|BC001410.1|BC001410 682 577 0 354/356 Homo sapiens, S100 calcium-binding protein A11 (calgizzarin), clone MGC: 2149, mRNA, complete cds 161 175 BC001308 gi|12654922|gb|BC001308.1|BC001308 646 2263 0 353/362 Homo sapiens, clone HQ0310 PRO0310p1, clone MGC: 5505, mRNA, complete cds 162 176 XM_009004 gi|12742171|ref|XM_009004.2| Homo 458 1448 1E−127 231/231 sapiens kallikrein 10 (KLK10), mRNA 163 177 XM_006705 gi|12737366|ref|XM_006705.2| Homo 630 784 1E−179 324/326 sapiens nascent-polypeptide-associated complex alpha polypeptide (NACA), mRNA 164 178 AF102848 gi|12641918|gb|AF102848.1|AF102848 739 1649 0 379/381 Homo sapiens keratin 23 (KRT23) mRNA, complete cds 165 179 XM_003512 gi|12730699|ref|XM_003512.2| Homo 718 1231 0 371/374 sapiens amphiregulin (schwannoma- derived growth factor) (AREG), mRNA 166 180 XM_005313 gi|12734542|ref|XM_005313.2| Homo 652 1275 0 335/337 sapiens gamma-glutamyl hydrolase (conjugase, folylpolygammaglutamyl hydrolase) (GGH), mRNA 168 182 XM_010117 gi|11419764|ref|XM_010117.1| Homo 690 2519 0 360/364 sapiens plastin 3 (T isoform) (PLS3), mRNA 169 183 L47277 gi|986911|gb|L47277.1|HUMTOPATRA 646 994 0 353/362 Homo sapiens (cell line HepG2, HeLa) alpha topoisomerase truncated-form mRNA, 3′UTR 170 184 XM_012941 gi|12742342|ref|XM_012941.1| Homo 670 3071 0 341/342 sapiens chromosome 20 open reading frame 1 (C20ORF1), mRNA 171 185 NM_000581 gi|10834975|ref|NM_000581.1| Homo 640 1134 0 339/343 sapiens glutathione peroxidase 1 (GPX1), mRNA 172 185 NM_000581 gi|10834975|ref|NM_000581.1| Homo 640 1134 0 338/343 sapiens glutathione peroxidase 1 (GPX1), mRNA 173 186 X06705 gi|35511|emb|X06705.1|HSPLAX 700 883 0 353/353 Human PLA-X mRNA 174 187 D45915 gi|1483130|dbj|D45915.1|D45915 666 2584 0 336/336 Human mRNA for p80 protein, complete cds 176 189 BC000242 gi|12652962|gb|BC000242.1|BC000242 521 849 1E−146 280/286 Homo sapiens, CGI-138 protein, clone MGC: 676, mRNA, complete cds 177 190 BC005945 gi|13543585|gb|BC005945.1|BC005945 567 1391 1E−160 295/298 Homo sapiens, MAD2 (mitotic arrest deficient, yeast, homolog)-like 1, clone MGC: 14577, mRNA, complete cds 179 192 XM_010835 gi|12728550|ref|XM_010835.1| Homo 452 1679 1E−125 313/340 sapiens similar to hypothetical protein (H. sapiens) (LOC65349), mRNA 180 193 XM_009475 gi|11420562|ref|XM_009475.1| Homo 668 2110 0 340/341 sapiens S-adenosylhomocysteine hydrolase (AHCY), mRNA 181 194 AF054183 gi|4092053|gb|AF054183.1|AF054183 690 1148 0 351/352 Homo sapiens GTP binding protein mRNA, complete cds 182 195 BC005356 gi|13529175|gb|BC005356.1|BC005356 396 1050 1E−108 200/200 Homo sapiens, Similar to hypothetical protein MGC3077, clone MGC: 12457, mRNA, complete cds 183 196 XM_006545 gi|12736918|ref|XM_006545.2| Homo 613 588 1E−173 309/309 sapiens hypothetical protein (HSPC152), mRNA 184 197 XM_003598 gi|12730828|ref|XM_003598.2| Homo 662 440 0 345/349 sapiens S100 calcium-binding protein P (S100P), mRNA 185 197 NM_005980 gi|5174662|ref|NM_005980.1| Homo 565 439 1E−159 291/293 sapiens S100 calcium-binding protein P (S100P), mRNA 190 199 M80340 gi|339767|gb|M80340.1|HUMTNL12 539 6075 1E−151 351/377 Human transposon L1.1 with a base deletion relative to L1.2B resulting in a premature stop codon in the coding region 191 199 U93574 gi|2072975|gb|U93574.1|HSU93574 404 5979 1E−111 290/318 Human L1 element L1.39 p40 and putative p150 genes, complete cds 192 200 AC002143 gi|2168303|gb|AC002143.1|AC002143 214 4025 8E−54 235/275 Homo sapiens (subclone 4_b10 from BAC H102) DNA sequence, complete sequence 193 176 BC002710 gi|12803744|gb|BC002710.1|BC002710 648 1542 0 327/327 Homo sapiens, kallikrein 10, clone MGC: 3667, mRNA, complete cds 194 201 XM_004286 gi|11418526|ref|XM_004286.1| Homo 561 700 1E−158 289/291 sapiens ribosomal protein L10a (RPL10A), mRNA 196 118 AF226998 gi|12655885|gb|AF226998.1|AF226998 505 734 1E−141 255/255 Homo sapiens dpy-30-like protein mRNA, complete cds 198 204 AL3900221 gi|10862787|emb|AL390022.11|AL390022 470 9277 1E−130 337/369 Human DNA sequence from clone RP11-370B6 on chromosome X, complete sequence [Homo sapiens] 200 206 BC002476 gi|12803316|gb|BC002476.1|BC002476 615 695 1E−174 316/318 Homo sapiens, non-metastatic cells 2, protein (NM23B) expressed in, clone MGC: 2212, mRNA, complete cds 201 207 XM_005235 gi|12734360|ref|XM_005235.2| Homo 605 1507 1E−171 311/313 sapiens eukaryotic translation initiation factor 3, subunit 6 (48 kD) (EIF3S6), mRNA 202 152 BC004427 gi|13325215|gb|BC004427.1|BC004427 611 967 1E−173 321/324 Homo sapiens, proteasome (prosome, macropain) subunit, alpha type, 7, clone MGC: 3755, mRNA, complete cds 204 151 AK024303 gi|10436651|dbj|AK024303.1|AK024303 585 1591 1E−165 295/295 Homo sapiens cDNA FLJ14241 fis, clone OVARC1000533 205 151 AK024303 gi|10436651|dbj|AK024303.1|AK024303 591 1591 1E−167 298/298 Homo sapiens cDNA FLJ14241 fis, clone OVARC1000533 206 153 XM_003927 gi|11417090|ref|XM_003927.1| Homo 656 473 0 337/339 sapiens Apg12 (autophagy 12, S. cerevisiae)- like (APG12L), mRNA 207 154 BC000947 gi|13111828|gb|BC000947.2|BC000947 644 1608 0 336/340 Homo sapiens, clone IMAGE: 3450586, mRNA, partial cds 208 155 XM_004478 gi|12732587|ref|XM_004478.2| Homo 660 1993 0 339/341 sapiens glyoxalase I (GLO1), mRNA 209 156 L36587 gi|598241|gb|L36587.1|HUMUHGA 664 1357 0 335/335 Homo sapiens spliced UHG RNA 210 157 BC000447 gi|12653354|gb|BC000447.1|BC000447 656 585 0 334/335 Homo sapiens, macrophage migration inhibitory factor (glycosylation- inhibiting factor), clone MGC: 8444, mRNA, complete cds 211 158 BC001708 gi|12804576|gb|BC001708.1|BC001708 626 906 1E−178 319/320 Homo sapiens, ribosomal protein S3A, clone MGC: 1626, mRNA, complete cds 212 159 BC005008 gi|13477106|gb|BC005008.1|BC005008 668 2249 0 337/337 Homo sapiens, carcinoembryonic antigen-related cell adhesion molecule 6 (non-specific cross reacting antigen), clone MGC: 10467, mRNA, complete cds 213 160 AL110141 gi|5817036|emb|AL110141.1|HSM800785 519 656 1E−145 265/266 Homo sapiens mRNA; cDNA DKFZp564D0164 (from clone DKFZp564D0164) 214 161 NM_014366 gi|7657047|ref|NM_014366.1| Homo 634 2059 1E−180 335/343 sapiens putative nucleotide binding protein, estradiol-induced (E2IG3), mRNA 215 162 AL359585 gi|8655645|emb|AL359585.1|HSM802687 129 2183 4E−28 68/69 Homo sapiens mRNA; cDNA DKFZp762B195 (from clone DKFZp762B195) 217 195 NM_024051 gi|13129017|ref|NM_024051.1| Homo 646 1195 0 329/330 sapiens hypothetical protein MGC3077 (MGC3077), mRNA 218 164 XM_006551 gi|11441541|ref|XM_006551.1| Homo 601 905 1E−170 321/327 sapiens interferon induced transmembrane protein 2 (1-8D) (IFITM2), mRNA 220 65 XM_007736 gi|11433251|ref|XM_007736.1| Homo 648 836 0 330/331 sapiens KIAA0101 gene product (KIAA0101), mRNA 222 124 U07571 gi|497170|gb|U07571.1|HSU07571 46.1 392 0.005 23/23 Human clone S1X13-SS13A dinucleotide repeat at Xq21 223 126 AF288394 gi|12620197|gb|AF288394.1|AF288394 718 1961 0 377/382 Homo sapiens C1orf19 mRNA, partial cds 224 132 U35622 gi|5733846|gb|U35622.2|HSU35622 779 2107 0 398/400 Homo sapiens EWS protein/E1A enhancer binding protein chimera mRNA, complete cds 225 291 BC004928 gi|13436256|gb|BC004928.1|BC004928 793 2567 0 400/400 Homo sapiens, clone MGC: 10493, mRNA, complete cds 226 142 AL137736 gi|6808315|emb|AL137736.1|HSM802318 692 2053 0 363/365 Homo sapiens mRNA; cDNA DKFZp586P2321 (from clone DKFZp586P2321) 227 144 XM_008130 gi|11424226|ref|XM_008130.1| Homo 785 1361 0 396/396 sapiens galactokinase 1 (GALK1), mRNA 228 115 AF019770 gi|2674084|gb|AF019770.1|AF019770 1370 1202 0 721/729 Homo sapiens macrophage inhibitory cytokine-1 (MIC-1) mRNA, complete cds 230 255 AF179710 gi|9836821|gb|AF179710.1|AF179710 40.1 1096 0.35 20/20 Pongo pygmaeus RH50 glycoprotein (RHAG) gene, intron 9 231 262 XM_009943 gi|11418022|ref|XM_009943.1| Homo 864 5486 0 455/462 sapiens tissue inhibitor of metalloproteinase 3 (Sorsby fundus dystrophy, pseudoinflammatory) (TIMP3), mRNA 232 256 AF134904 gi|4809150|gb|AF134904.1|AF134904 42.1 2558 0.097 21/21 Schistocerca gregaria semaphorin 2a mRNA, complete cds 233 263 BC003002 gi|12804286|gb|BC003002.1|BC003002 523 2165 1E−147 284/294 Homo sapiens, polo (Drosophia)-like kinase, clone MGC: 3988, mRNA, complete cds 234 265 M68513 gi|199119|gb|M68513.1|MUSMEK4 882 3197 0 491/503 Mouse eph-related receptor tyrosine kinase (Mek4) mRNA, complete cds 235 264 XM_007931 gi|12739533|ref|XM_007931.2| Homo 730 1593 0 407/414 sapiens solute carrier family 9 (sodium/hydrogen exchanger), isoform 3 regulatory factor 2 (SLC9A3R2), mRNA 236 266 XM_003748 gi|12731108|ref|XM_003748.2| Homo 387 2967 1E−106 267/302 sapiens serum-inducible kinase (SNK), mRNA 239 269 BC001401 gi|12655098|gb|BC001401.1|BC001401 773 1571 0 396/398 Homo sapiens, Similar to sterile-alpha motif and leucine zipper containing kinase AZK, clone MGC: 808, mRNA, complete cds 240 270 S76617 gi|914203|gb|S76617.1|S76617 38.2 2608 0.87 19/19 blk = protein tyrosine kinase [human, B lymphocytes, mRNA, 2608 nt] 242 273 AK006144 gi|12839086|dbj|AK006144.1|AK006144 323 1387 1E−86 233/255 Mus musculus adult male testis cDNA, RIKEN full-length enriched library, clone: 1700020B19, full insert sequence 243 276 X91656 gi|2125862|emb|X91656.1|MMSRP20 494 13121 1E−138 262/265 M. musculus Srp20 gene 247 236 BC002499 gi|12803360|gb|BC002499.1|BC002499 640 2129 0 330/331 Homo sapiens, serine/threonine kinase 15, clone MGC: 1605, mRNA, complete cds 248 277 NM_003618 gi|4506376|ref|NM_003618.1|Homo 702 4380 0 361/362 sapiens mitogen-activated protein kinase kinase kinase kinase 3 (MAP4K3), mRNA 249 278 NM_018492 gi|8923876|ref|NM_018492.1|Homo 779 1548 0 400/401 sapiens PDZ-binding kinase; T-cell originated protein kinase (TOPK), mRNA 250 278 XM_005110 gi|12734111|ref|XM_005110.2|Homo 1003 1537 0 506/506 sapiens PDZ-binding kinase; T-cell originated protein kinase (TOPK), mRNA 252 274 BC002466 gi|12803300|gb|BC002466.1|BC002466 1074 2451 0 575/581 Homo sapiens, v-raf murine sarcoma 3611 viral oncogene homolog 1, clone MGC: 2356, mRNA, complete cds 253 280 XM_001729 gi|11423735|ref|XM_001729.1|Homo 751 1658 0 385/387 sapiens v-akt murine thymoma viral oncogene homolog 3 (protein kinase B, gamma) (AKT3), mRNA 254 259 NM_002893 gi|13259504|ref|NM_002893.2|Homo 1164 1946 0 715/746 sapiens retinoblastoma-binding protein 7 (RBBP7), mRNA 255 210 AB056798 gi|13365896|dbj|AB056798.1|AB056798 678 4521 0 435/461 Macaca fascicularis brain cDNA clone: QflA-11110, full insert sequence 256 213 AJ302649 gi|11140019|emb|AJ302649.1|DRE302649 42.1 2188 0.058 21/21 Danio rerio mRNA for GABAA receptor betaZ2 subunit (gabaabeta2 gene) 257 212 L27711 gi|808006|gb|L27711.1|HUMKAP1A 1057 844 0 550/553 Human protein phosphatase (KAP1) mRNA, complete cds 258 214 NM_004336 gi|4757877|ref|NM_004336.1|Homo 1318 3446 0 694/701 sapiens budding uninhibited by benzimidazoles 1 (yeast homolog) (BUB1), mRNA 260 216 NM_004300 gi|4757713|ref|NM_004300.1|Homo 985 2222 0 621/656 sapiens acid phosphatase 1, soluble (ACP1), transcript variant a, mRNA 262 219 AK026166 gi|10438929|dbj|AK026166.1|AK026166 1402 1813 0 838/871 Homo sapiens cDNA: FLJ22513 fis, clone HRC12111, highly similar to HUMKUP Human Ku (p70/p80) subunit mRNA 263 252 BC004937 gi|13436283|gb|BC004937.1|BC004937 898 1032 0 475/480 Homo sapiens, clone MGC: 10779, mRNA, complete cds 264 220 XM_006375 gi|12736706|ref|XM_006375.2|Homo 1316 737 0 693/703 sapiens glutathione S-transferase pi (GSTP1), mRNA 265 218 BC001827 gi|12804774|gb|BC001827.1|BC001827 1259 1073 0 672/683 Homo sapiens, Similar to deoxythymidylate kinase (thymidylate kinase), clone MGC: 3923, mRNA, complete cds 266 221 BC002900 gi|12804094|gb|BC002900.1|BC002900 1217 867 0 699/728 Homo sapiens, Similar to proteasome (prosome, macropain) subunit, alpha type, 2, clone IMAGE: 3942625, mRNA, partial cds 267 226 AF064029 gi|4091894|gb|AF064029.1|AF064029 60 779 0.0000002 30/30 Helianthus tuberosus lectin 1 mRNA, complete cds 268 212 L27711 gi|808006|gb|L27711.1|HUMKAP1A 1257 844 0 694/705 Human protein phosphatase (KAP1) mRNA, complete cds 269 223 XM_011470 gi|12732420|ref|XM_011470.1|Homo 1029 2591 0 519/519 sapiens myristoylated alanine-rich protein kinase C substrate (MARCKS, 80K-L) (MACS), mRNA 270 221 BC002900 gi|12804094|gb|BC002900.1|BC002900 1330 867 0 724/739 Homo sapiens, Similar to proteasome (prosome, macropain) subunit, alpha type, 2, clone IMAGE: 3942625, mRNA, partial cds 271 206 BC002476 gi|12803316|gb|BC002476.1|BC002476 1203 695 0 610/611 Homo sapiens, non-metastatic cells 2, protein (NM23B) expressed in, clone MGC: 2212, mRNA, complete cds 272 225 XM_007980 gi|12739602|ref|XM_007980.2| Homo 904 1866 0 481/487 sapiens membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase (PKMYT1), mRNA 273 231 S50810 gi|262070|gb|S50810.1|S50810 {satellite 52 1086 0.00003 29/30 DNA} [Drosophila melanogaster, Doc mobile element, Transposon, 1086 nt] 274 233 AF217396 gi|8132773|gb|AF217396.1|AF217396 46.1 2007 0.004 23/23 Drosophila melanogaster clone 2G2 unknown mRNA 275 232 L29057 gi|609636|gb|L29057.1|XELCADH 40.1 4097 0.081 20/20 Xenopus laevis (clone: XTCAD-1) cadherin gene, complete cds 276 227 XM_008475 gi|11426657|ref|XM_008475.1| Homo 40.1 6962 0.32 20/20 sapiens KIAA0100 gene product (KIAA0100), mRNA 277 229 M34230 gi|204651|gb|M34230.1|RATHPA1 Rat 56 3282 0.000002 28/28 haptoglobin (Hp) gene, exons 1, 2 and 3 278 230 AJ302649 gi|11140019|emb|AJ302649.1|DRE302649 50.1 2188 0.0002 25/25 Danio rerio mRNA for GABAA receptor betaZ2 subunit (gabaabeta2 gene) 279 239 NM_021158 gi|11056039|ref|NM_021158.1| Homo 710 2257 0 358/358 sapiens protein kinase domains containing protein similar to phosphoprotein C8FW (LOC57761), mRNA 280 238 AX030958 gi|10278361|emb|AX030958.1|AX030958 56 3828 0.000005 28/28 Sequence 7 from Patent WO9800549 281 228 XM_010102 gi|11419709|ref|XM_010102.1| Homo 1469 1767 0 839/865 sapiens phosphoglycerate kinase 1 (PGK1), mRNA 282 235 U00238 gi|404860|gb|U00238.1|U00238 Homo 1132 3600 0 653/677 sapiens glutamine PRPP amidotransferase (GPAT) mRNA, complete cds 283 237 NM_002753 gi|4506080|ref|NM_002753.1| Homo 733 2372 0 381/385 sapiens mitogen-activated protein kinase 10 (MAPK10), mRNA 284 241 XM_006151 gi|12736568|ref|XM_006151.2| Homo 979 1640 0 494/494 sapiens similar to serine protease, umbilical endothelium (H. sapiens) (LOC63320), mRNA 285 242 BC004215 gi|13278917|gb|BC004215.1|BC004215 1106 3373 0 578/585 Homo sapiens, eukaryotic translation elongation factor 1 gamma, clone MGC: 4501, mRNA, complete cds 286 243 NM_000455 gi|4507270|ref|NM_000455.1| Homo 1243 2158 0 651/660 sapiens serine/threonine kinase 11 (Peutz-Jeghers syndrome) (STK11), mRNA 287 258 XM_004842 gi|12733228|ref|XM_004842.2| Homo 682 3715 0 381/387 sapiens SFRS protein kinase 2 (SRPK2), mRNA 288 261 NM_020197 gi|9910273|ref|NM_020197.1| Homo 561 1694 1E−158 346/355 sapiens HSKM-B protein (HSKM-B), mRNA 289 260 XM_001416 gi|12719345|ref|XM_001416.2| Homo 517 2966 1E−145 277/284 sapiens similar to ribosomal protein S6 kinase, 90 kD, polypeptide 1 (H. sapiens) (LOC65290), mRNA 290 236 BC002499 gi|12803360|gb|BC002499.1|BC002499 618 2129 1E−175 358/366 Homo sapiens, serine/threonine kinase 15, clone MGC: 1605, mRNA, complete cds 293 246 XM_004679 gi|11419466|ref|XM_004679.1| Homo 383 987 1E−104 214/224 sapiens cyclin-dependent kinase 5 (CDK5), mRNA 294 245 XM_005258 gi|11426310|ref|XM_005258.1| Homo 902 2391 0 463/466 sapiens serum/glucocorticoid regulated kinase-like (SGKL), mRNA 295 248 XM_008654 gi|12740227|ref|XM_008654.2| Homo 662 3576 0 369/374 sapiens mitogen-activated protein kinase kinase 4 (MAP2K4), mRNA 296 129 BC002364 gi|12803120|gb|BC002364.1|BC002364 688 2645 0 347/347 Homo sapiens, non-POU-domain- containing, octamer-binding, clone MGC: 8677, mRNA, complete cds 298 2 NM_004443 gi|4758287|ref|NM_004443.1| Homo 533 3805 1E−150 297/301 sapiens EphB3 (EPHB3) mRNA 299 254 XM_002383 gi|11429253|ref|XM_002383.1| Homo 571 2832 1E−161 333/340 sapiens activin A receptor, type I (ACVR1), mRNA 300 249 BC000633 gi|12653696|gb|BC000633.1|BC000633 537 2993 1E−151 396/419 Homo sapiens, TTK protein kinase, clone MGC: 865, mRNA, complete cds 301 2 NM_004443 gi|4758287|ref|NM_004443.1| Homo 795 3805 0 453/467 sapiens EphB3 (EPHB3) mRNA 302 224 XM_005116 gi|12734122|ref|XM_005116.2| Homo 470 3396 1E−131 252/259 sapiens protein tyrosine kinase 2 beta (PTK2B), mRNA 303 222 AB056389 gi|13358639|dbj|AB056389.1|AB056389 196 2038 9E−49 129/141 Macaca fascicularis brain cDNA, clone: QflA-12365 304 208 BC002921 gi|12804134|gb|BC002921.1|BC002921 446 2349 1E−123 260/274 Homo sapiens, Similar to protein kinase related to S. cerevisiae STE20, effector for Cdc42Hs, clone MGC: 10333, mRNA, complete cds 305 250 XM_004079 gi|11417431|ref|XM_004079.1| Homo 525 1719 1E−147 275/280 sapiens serine/threonine-protein kinase PRP4 homolog (PRP4), mRNA 306 251 XM_004306 gi|11418576|ref|XM_004306.1| Homo 317 7375 4E−85 160/160 sapiens v-ros avian UR2 sarcoma virus oncogene homolog 1 (ROS1), mRNA 307 252 BC004937 gi|13436283|gb|BC004937.1|BC004937 975 1032 0 567/582 Homo sapiens, clone MGC: 10779, mRNA, complete cds 308 253 NM_006293 gi|5454141|ref|NM_006293.1| Homo 823 4364 0 457/466 sapiens TYRO3 protein tyrosine kinase (TYRO3), mRNA 309 257 X71765 gi|402221|emb|X71765.1|PFCAATPAS 38.2 5477 1.4 19/19 P. falciparum gene for Ca2+ - ATPase

Example 2 Detection of Differential Expressions Using Arrays

mRNA isolated from samples of cancerous and normal colon tissue obtained from patients were analyzed to identify genes differentially expressed in cancerous and normal cells. Normal and cancerous cells collected from cryopreserved patient tissues were isolated using laser capture microdissection (LCM) techniques, which techniques are well known in the art (see, e.g., Ohyama et al. (2000) Biotechniques 29:530-6; Curran et al. 2000) Mol. Pathol. 53:64-8; Suarez-Quian et al. (1999) Biotechniques 26:328-35; Simone et al. (1998) Trends Genet 14:272-6; Conia et al. (1997) J. Clin. Lab. Anal. 11:28-38; Emmert-Buck et al. (1996) Science 274:998-1001).

Tables 4A and 4B (inserted before the claims) provides information about each patient from which the samples were isolated, including: the “Patient ID” and “Path ortID”, which are numbers assigned to the patient and the pathology reports for identification purposes; the “Group” to which the patients have been assigned; the anatomical location of the tumor (“Anatom Loc”); the “Primary Tumor Size”; the “Primary Tumor Grade”; the identification of the histopathological grade (“Histopath Grade”); a description of local sites to which the tumor had invaded (“Local Invasion”); the presence of lymph node metastases (“Lymph Node Met”); the incidence of lymph node metastases (provided as a number of lymph nodes positive for metastasis over the number of lymph nodes examined) (“Incidence Lymphnode Met”); the “Regional Lymphnode Grade”; the identification or detection of metastases to sites distant to the tumor and their location (“Distant Met & Loc”); a description of the distant metastases (“Descrip Distant Met”); the grade of distant metastasis (“Dist Met Grade”); and general comments about the patient or the tumor (“Comments”). Adenoma was not described in any of the patients; adenoma dysplasia (described as hyperplasia by the pathologist) was described in Patient ID No. 695. Extranodal extensions were described in two patients, Patient ID Nos. 784 and 791. Lymphovascular invasion was described in seven patients, Patient ID Nos. 128, 278, 517, 534, 784, 786, and 791. Crohn's-like infiltrates were described in seven patients, Patient ID Nos. 52, 264, 268, 392, 393, 784, and 791. TABLE 4A Path Primary Primary Patient Report Tumor Tumor Histopath ID ID Group Anatom Loc Size Grade Grade Local Invasion 15 21 III Ascending 4 T3 G2 extending into colon subserosal adipose tissue 52 71 II Ascending 9 T3 G3 Invasion through colon muscularis propria, subserosal involvement; ileocec. valve involvement 121 140 II Sigmoid 6 T4 G2 Invasion of muscularis propria into serosa, involving submucosa of urinary bladder 125 144 II Cecum 6 T3 G2 Invasion through the muscularis propria into suserosal adipose tissue. Ileocecal junction. 128 147 III Transverse 5 T3 G2 Invasion of colon muscularis propria into percolonic fat 130 149 Splenic 5.5 T3 through wall and into flexure surrounding adipose tissue 133 152 II Rectum 5 T3 G2 Invasion through muscularis propria into non- peritonealized pericolic tissue; gross configuration is annular. 141 160 IV Cecum 5.5 T3 G2 Invasion of muscularis propria into pericolonic adipose tissue, but not through serosa. Arising from tubular adenoma. 156 175 III Hepatic 3.8 T3 G2 Invasion through flexure mucsularis propria into subserosa/pericolic adipose, no serosal involvement. Gross configuration annular. 228 247 III Rectum 5.8 T3 G2 to G3 Invasion through muscularis propria to involve subserosal, perirectoal adipose, and serosa 264 283 II Ascending 5.5 T3 G2 Invasion through colon muscularis propria into subserosal adipose tissue. 266 285 III Transverse 9 T3 G2 Invades through colon muscularis propria to involve pericolonic adipose, extends to serosa. 268 287 I Cecum 6.5 T2 G2 Invades full thickness of muscularis propria, but mesenteric adipose free of malignancy 278 297 III Rectum 4 T3 G2 Invasion into perirectal adipose tissue. 295 314 II Ascending 5 T3 G2 Invasion through colon muscularis propria into percolic adipose tissue. 339 358 II Rectosigmoid 6 T3 G2 Extends into perirectal fat but does not reach serosa 341 360 II Ascending 2 cm T3 G2 Invasion through colon invasive muscularis propria to involve pericolonic fat. Arising from villous adenoma. 356 375 II Sigmoid 6.5 T3 G2 Through colon wall into subserosal adipose tissue. No serosal spread seen. 360 412 III Ascending 4.3 T3 G2 Invasion thru colon muscularis propria to pericolonic fat 392 444 IV Ascending 2 T3 G2 Invasion through colon muscularis propria into subserosal adipose tissue, not serosa. 393 445 II Cecum 6 T3 G2 Cecum, invades through muscularis propria to involve subserosal adipose tissue but not serosa. 413 465 IV Ascending 4.8 T3 G2 Invasive through colon muscularis to involve periserosal fat; abutting ileocecal junction. 505 383 IV 7.5 cm T3 G2 Invasion through max dim muscularis propria involving pericolic adipose, serosal surface uninvolved 517 395 IV Sigmoid 3 T3 G2 penetrates muscularis propria, involves pericolonic fat. 534 553 II Ascending 12 T3 G3 Invasion through the colon muscularis propria involving pericolic fat. Serosa free of tumor. 546 565 IV Ascending 5.5 T3 G2 Invasion through colon muscularis propria extensively through submucosal and extending to serosa. 577 596 II Cecum 11.5 T3 G2 Invasion through the bowel wall, into suberosal adipose. Serosal surface free of tumor. 695 714 II Cecum 14 T3 G2 extending through bowel wall into serosal fat 784 803 IV Ascending 3.5 T3 G3 through muscularis colon propria into pericolic soft tissues 786 805 IV Descending 9.5 T3 G2 through muscularis colon propria into pericolic fat, but not at serosal surface 791 810 IV Ascending 5.8 T3 G3 through the colon muscularis propria into pericolic fat 888 908 IV Ascending 2 T2 G1 into muscularis colon propria 889 909 IV Cecum 4.8 T3 G2 through muscularis propria int subserosal tissue

TABLE 4B Incidence Regional Descrip Dist Patient Lymphnode Lymphnode Lympnode Distant Met Distant Met ID Met Met Grade & Loc Met Grade Comment 15 positive 8-Mar N1 negative MX invasive adenocarcinoma, moderately differentiated; focal perineural invasion is seen 52 negative 0/12 N0 negative M0 Hyperplastic polyp in appendix. 121 negative 0/34 N0 negative M0 Perineural invasion; donut anastomosis negative. One tubulovillous and one tubular adenoma with no high grade dysplasia. 125 negative 0/19 N0 negative M0 patient history of metastatic melanoma 128 positive 5-Jan N1 negative M0 130 positive 24-Oct N2 negative M1 133 negative 0/9 N0 negative M0 Small separate tubular adenoma (0.4 cm) 141 positive 21-Jul N2 positive adenocarcinoma M1 Perineural invasion (Liver) consistant identified adjacent to with metastatic primary adenocarcinoma. 156 positive 13-Feb N1 negative M0 Separate tubolovillous and tubular adenomas 228 positive 8-Jan N1 negative MX Hyperplastic polyps 264 negative 0/10 N0 negative M0 Tubulovillous adenoma with high grade dysplasia 266 negative 0/15 N1 positive 0.4 cm, MX (Mesenteric may deposit) represent lymphnode completely replaced by tumor 268 negative 0/12 N0 negative M0 278 positive 10-Jul N2 negative M0 Descending colon polyps, no HGD or carcinoma identified. 295 negative 0/12 N0 negative M0 Melanosis coli and diverticular disease. 339 negative 0/6 N0 negative M0 1 hyperplastic polyp identified 341 negative 0/4 N0 negative MX 356 negative 0/4 N0 negative M0 360 positive 5-Jan N1 negative M0 Two mucosal polyps 392 positive 6-Jan N1 positive Macrovesicular M1 Tumor arising at (Liver) and prior ileocolic microvesicular surgical anastomosis. steatosis 393 negative 0/21 N0 negative M0 413 negative 0/7 N0 positive adenocarcinoma M1 rediagnosis of (Liver) in oophorectomy path to multiple metastatic colon slides cancer. 505 positive 17-Feb N1 positive moderately M1 Anatomical location (Liver) differentiated of primary not adenocarcinoma, notated in report. consistant Evidence of chronic with colitis. primary 517 positive 6-Jun N2 negative M0 No mention of distant met in report 534 negative 0/8 N0 negative M0 Omentum with fibrosis and fat necrosis. Small bowel with acute and chronic serositis, focal abscess and adhesions. 546 positive 12-Jun N2 positive metastatic M1 (Liver) adenocarcinoma 577 negative 0/58 N0 negative M0 Appendix dilated and fibrotic, but not involved by tumor 695 negative 0/22 N0 negative MX tubular adenoma and hyperplstic polyps present, moderately differentiated adenoma with mucinous diferentiation (% not stated) 784 positive 17-May N2 positive M1 invasive poorly (Liver) differentiated adenosquamous carcinoma 786 negative 0/12 N0 positive M1 moderately (Liver) differentiated invasive adenocarcinoma

Identification of Differentially Expressed Genes

cDNA probes were prepared from total RNA isolated from the patient cells described above. Since LCM provides for the isolation of specific cell types to provide a substantially homogenous cell sample, this provided for a similarly pure RNA sample.

Total RNA was first reverse transcribed into cDNA using a primer containing a T7 RNA polymerase promoter, followed by second strand DNA synthesis. cDNA was then transcribed in vitro to produce antisense RNA using the T7 promoter-mediated expression (see, e.g., Luo et al. (1999) Nature Med 5:117-122), and the antisense RNA was then converted into cDNA. The second set of cDNAs were again transcribed in vitro, using the T7 promoter, to provide antisense RNA. Optionally, the RNA was again converted into cDNA, allowing for up to a third round of T7-mediated amplification to produce more antisense RNA. Thus the procedure provided for two or three rounds of in vitro transcription to produce the final RNA used for fluorescent labeling.

Fluorescent probes were generated by first adding control RNA to the antisense RNA mix, and producing fluorescently labeled cDNA from the RNA starting material. Fluorescently labeled cDNAs prepared from the tumor RNA sample were compared to fluorescently labeled cDNAs prepared from normal cell RNA sample. For example, the cDNA probes from the normal cells were labeled with Cy3 fluorescent dye (green) and the cDNA probes prepared from the tumor cells were labeled with Cy5 fluorescent dye (red), and vice versa.

Each array used had an identical spatial layout and control spot set. Each microarray was divided into two areas, each area having an array with, on each half, twelve groupings of 32×12 spots, for a total of about 9,216 spots on each array. The two areas are spotted identically which provide for at least two duplicates of each clone per array.

Polynucleotides for use on the arrays were obtained from both publicly available sources and from cDNA libraries generated from selected cell lines and patient tissues. PCR products of from about 0.5 kb to 2.0 kb amplified from these sources were spotted onto the array using a Molecular Dynamics Gen III spotter according to the manufacturer's recommendations. The first row of each of the 24 regions on the array had about 32 control spots, including 4 negative control spots and 8 test polynucleotides. The test polynucleotides were spiked into each sample before the labeling reaction with a range of concentrations from 2-600 pg/slide and ratios of 1:1. For each array design, two slides were hybridized with the test samples reverse-labeled in the labeling reaction. This provided for about four duplicate measurements for each clone, two of one color and two of the other, for each sample.

Table 5 (inserted before the claims) describes the physical location of the differentially expressed polynucleotides on the arrays. Table 5 includes: 1) a Spot ID, which is a unique identifier for each spot containing target sequence of interest on all arrays used; 2) a “Chip Num” which refers to a particular array representing a specific set of genes; 3) the “Sample Name or Clone Name” from which the sequence was obtained; and 4) the coordinates of the sequence on the particular array (“Coordinates”). Table 9 (inserted before the claims) provides information about the sequences on the arrays, specifically: 1) Candidate Identification Number; 2) Sample name or clone name; 3) function of the gene corresponding to the sequence (as determined by homology to genes of known function by BLAST search of GenBank); 4) the class of the gene (as determined by homology to genes of known function by BLAST search of GenBank); 5) the pathway in which the gene is implicated; 6) gene assignment; which refers to the gene to which the sequence has the greatest homology or identity; 7) the “Gene Symbol”; 8) chromosome number on which the gene is located (“Chrom Num”); 9) the map position on the chromosome. TABLE 5 Chip Sample Name or SpotID Num Clone Name Coords 27 1 M00023371A:G03 1:85 195 1 M00001489B:G04 1:227 212 1 M00026888A:A03 1:244 335 1 M00001558C:B06 1:367 511 1 M00003852B:C01 2:191 538 1 M00022009A:A12 2:218 599 1 M00001374A:A06 2:279 943 1 M00001341B:A11 3:271 1048 1 M00007965C:G08 3:376 1160 1 M00022140A:E11 4:136 1176 1 M00022180D:E11 4:152 1195 1 M00001675B:G05 4:171 1203 1 M00003853B:G11 4:179 1252 1 M00022742A:F08 4:228 1266 1 M00026900D:F02 4:242 1605 1 M00001496A:G03 5:229 1648 1 M00001393D:F01 5:272 1793 1 M00023283C:C06 6:65 1927 1 M00007985A:B08 6:199 1933 1 M00007985B:A03 6:205 2332 1 M00026903D:D11 7:252 2404 1 M00006883D:H12 7:324 2633 1 M00007987D:D04 8:201 2659 1 M00023431B:A01 8:227 2662 1 M00023363C:A04 8:230 2799 1 M00004031B:D12 8:367 2889 1 M00003814C:C11 9:105 2917 1 M00007935D:A05 9:133 3005 1 M00021956B:A09 9:221 3204 1 M00027066B:E09 10:68 3296 1 M00022215C:A10 10:160 3313 1 M00003961B:H05 10:177 3519 1 M00005360A:A07 10:383 3665 1 M0001600C:B11 11:177 3748 1 M00001402B:C12 11:260 3974 1 M00022168B:F02 12:134 4040 1 M00008049B:A12 12:200 8594 2 RG:742775:10011:A07 1:178 8630 2 I:2458926:03B01:C07 1:214 8788 2 I:3229778:02B01:B07 1:372 8840 2 I:1857563:05B02:D01 2:72 9042 2 I:4072558:12B01:A07 2:274 9191 2 I:1421929:05A01:D02 3:71 9349 2 I:1723834:01A01:C02 3:229 9478 2 I:1817434:02B01:C02 3:358 9489 2 I:1750782:02A01:A08 3:369 9547 2 I:1297179:05A02:F02 4:75 9684 2 I:1443877:03B02:B08 4:212 9724 2 I:1384823:01B02:F08 4:252 9739 2 I:2902903:12A02:F02 4:267 9809 2 I:2152363:04A02:A08 4:337 10000 2 RG:813679:10011:H03 5:176 10006 2 RG:759927:10011:C09 5:182 10153 2 I:1712592:04A01:E03 5:329 10168 2 I:2615513:04B01:D09 5:344 10200 2 I:1702266:02B01:D09 5:376 10299 2 I:2825369:07A02:F09 6:123 10394 2 I:1450639:03B02:E09 6:218 10426 2 I:2499976:01B02:E09 6:250 10600 2 I:1749883:05B01:D04 7:72 10614 2 I:1516301:05B01:C10 7:86 10621 2 I:1298021:05A01:G10 7:93 10744 2 I:1613615:03B01:D10 7:216 10877 2 I:1395918:04A01:G10 7:349 10956 2 I:1600586:05B02:F04 8:76 10984 2 I:1666080:07B02:D04 8:104 11017 2 I:1633286:06A02:E04 8:137 11019 2 I:1609538:06A02:F04 8:139 11035 2 I:1630804:06A02:F10 8:155 11223 2 I:1749417:04A02:D10 8:343 11245 2 I:1809385:02A02:G04 8:365 11258 2 I:1854245:02B02:E10 8:378 11445 2 I:1854558:03A01:C11 9:213 11569 2 I:1509602:04A01:A11 9:337 11739 2 I:1699587:06A02:F11 10:155 11838 2 I:2840195:01B02:G11 10:254 11908 2 I:2914719:04B02:B05 10:324 11923 2 I:2239819:04A02:B11 10:339 12001 2 I:2483109:05A01:A06 11:65 12007 2 I:2499479:05A01:D06 11:71 12013 2 I:2675481:05A01:G06 11:77 12104 2 RG:773612:10011:D06 11:168 12270 2 I:2914605:04B01:G06 11:334 12513 2 I:2079906:01A02:A06 12:225 12519 2 I:1810640:01A02:D06 12:231 16933 3 I:1963753:18B01:E07 1:122 17035 3 RG:166410:10006:F01 1:171 17059 3 I:1920650:16A01:B01 1:195 17068 3 I:1923769:16B01:F01 1:204 17069 3 I:901317:16A01:G01 1:205 17075 3 I:3518380:16A01:B07 1:211 17171 3 RG:666323:10010:B07 1:307 17385 3 RG:244132:10007:E01 2:169 17386 3 RG:2117694:10016:E01 2:170 17399 3 RG:241029:10007:D07 2:183 17459 3 I:2056395:13A02:B07 2:243 17533 3 RG:1555877:10013:G07 2:317 17696 3 I:1923490:18B01:H08 3:128 17730 3 RG:526536:10002:A02 3:162 17742 3 RG:612874:10002:G02 3:174 17746 3 RG:530002:10002:A08 3:178 17836 3 RG:29739:10004:F02 3:268 17964 3 I:1920522:15B02:F02 4:44 18089 3 RG:244601:10007:E02 4:169 18100 3 RG:2048081:10016:B08 4:180 18102 3 RG:2097294:10016:C08 4:182 18240 3 RG:1927470:10015:H08 4:320 18331 3 I:1926006:15A01:F09 5:59 18379 3 I:2359588:18A01:F03 5:107 18389 3 I:986558:18A01:C09 5:117 18408 3 I:970933:14B01:D03 5:136 18445 3 RG:180296:10006:G03 5:173 18488 3 I:1743234:16B01:D09 5:216 18552 3 RG:25258:10004:D09 5:280 18580 3 RG:985973:10012:B09 5:308 18801 3 RG:203031:10007:A09 6:177 18804 3 RG:2055807:10016:B09 6:180 18856 3 I:605019:13B02:D03 6:232 18886 3 RG:43296:10005:C03 6:262 18903 3 RG:301608:10008:D09 6:279 18904 3 RG:45623:10005:D09 6:280 18921 3 RG:1461567:10013:E03 6:297 18942 3 RG:1895716:10015:G09 6:318 18985 3 I:1402615:09A02:E03 6:361 19067 3 I:2054678:19A01:F10 7:91 19120 3 I:956077:14B01:H04 7:144 19175 3 I:750899:16A01:D04 7:199 19189 3 I:620494:16A01:C10 7:213 19229 3 I:2060725:13A01:G10 7:253 19264 3 RG:35892:10004:H10 7:288 19374 3 I:1758241:15B02:G04 8:46 19428 3 I:1965257:18B02B04 8:100 19590 3 RG:43534:10005:C04 8:262 19600 3 RG:110764:10005:H04 8:272 19603 3 RG:278409:10008:B10 8:275 19604 3 RG:41097:10005:B10 8:276 19629 3 RG:1552386:10013:G04 8:301 19642 3 RG:1838677:10015:E10 8:314 19766 3 I:1996180:19B01:C11 9:86 19816 3 I:1431819:14B01:D05 9:136 19821 3 I:1833191:14A01:G05 9:141 19822 3 I:1227385:14B01:G05 9:142 19835 3 I:2055926:14A01:F11 9:155 19950 3 RG:32281:10004:G05 9:270 19962 3 RG:27403:10004:E11 9:282 19971 3 RG:665682:10010:B05 9:291 20102 3 I:2759046:19B02:C05 10:70 20196 3 RG:2012168:10016:B05 10:164 20280 3 I:1960722:13B02:D11 10:248 20303 3 RG:343821:10008:H05 10:271 20315 3 RG:323425:10008:F11 10:283 20506 3 I:1969044:18B01:E12 11:122 20586 3 I:659143:16B01:E06 11:202 20691 3 RG:669110:10010:B12 11:307 20703 3 RG:740831:10010:H12 11:319 20775 3 I:1968921:15A02:D06 12:39 20878 3 I:998612:14B02:G06 12:142 20915 3 RG:208954:10007:B12 12:179 20940 3 I:1967543:16B02:F06 12:204 21017 3 RG:306813:10008:E12 12:281 21025 3 RG:1353123:10013:A06 12:289 21068 3 I:549299:17B02:F:06 12:332 21160 4 RG:1996901:20003:D01 1:104 21207 4 M00056483D:G07 1:151 21294 4 M00042439D:C11 1:238 21354 4 RG:781507:10011:E01 1:298 21518 4 RG:1374447:20004:G01 2:110 21544 4 M00056908A:H05 2:136 21589 4 M00054777D:E09 2:181 21674 4 RG:2002384:20003:E01 2:266 21705 4 RG:1651303:10014:E01 2:297 21732 4 M00054538C:C01 2:324 21763 4 M00056622B:F12 2:355 21769 4 M00056632B:H10 2:361 21784 4 M00055423A:C07 2:376 21812 4 M00056308A:F02 3:52 21884 4 RG:2006302:20003:F08 3:124 21921 4 M00054639D:F05 3:161 21983 4 M00057081B:H03 3:223 22023 4 M00056533D:G07 3:263 22027 4 M00056534C:E08 3:267 22043 4 M00056585B:F04 3:283 22060 4 RG:785846:10011:F02 3:300 22072 4 RG:781028:10011:D08 3:312 22254 4 M00056918C:F09 4:142 22285 4 M00054742C:B12 4:173 22299 4 M00054806B:G03 4:187 22366 4 M00056350B:B03 4:254 22375 4 M00056728C:G02 4:263 22405 4 RG:1637619:10014:C02 4:293 22415 4 RG:1674393:10014:H02 4:303 22419 4 RG:1635546:10014:B08 4:307 22498 4 M00056250C:B02 5:34 22619 4 M00056500C:A07 5:155 22633 4 M00054647A:A09 5:169 22678 4 M00057231A:G04 5:214 22724 4 RG:1861510:20001:B03 5:260 22775 4 RG:417109:10009:D09 5:311 22783 4 RG:487171:10009:H09 5:319 23103 4 M00056810A:A02 6:287 23179 4 M00056645C:D11 6:363 23183 4 M00056646B:F07 6:367 23189 4 M00056679B:H03 6:373 23286 4 RG:1996788:20003:C10 7:118 23337 4 M00054650D:E04 7:169 23371 4 M00057044D:G03 7:203 23373 4 M00057046A:G09 7:205 23380 4 M00057241C:F03 7:212 23394 4 M00042756A:H02 7:226 23471 4 RG:471154:10009:H04 7:303 23514 4 M00054520A:D04 7:346 23803 4 M00056812D:A08 8:283 23813 4 RG:1638979:10014:C04 8:293 23984 4 RG:2051667:20003:H05 9:112 24185 4 RG:432960:10009:E11 9:313 24186 4 RG:785368:10011:E11 9:314 24297 4 M00055209C:B07 10:73 24358 4 M00056937C:C10 10:134 24394 4 M00056992C:F12 10:170 24423 4 M00057126C:B03 10:199 24429 4 M00057127B:B09 10:205 24515 4 RG:1630930:10014:B05 10:291 24519 4 RG:1645945:10014:D05 10:295 24700 4 RG:2006592:20003:F12 11:124 24713 4 M00056478D:B07 11:137 24728 4 M00056227B:G06 11:152 24806 4 M00042770D:G04 11:230 24855 4 M00056619A:H02 11:279 24866 4 RG:742764:10011:A06 11:290 24867 4 RG:364972:10009:B06 11:291 24883 4 RG:376554:10009:B12 11:307 24900 4 M00054500D:C08 11:324 24944 4 M00054971D:D07 11:368 25021 4 M00055258B:D12 12:93 25095 4 M00054769A:E05 12:167 25161 4 M00055435B:A12 12:233 25203 4 M00056822A:E08 12:275 25212 4 RG:2006592:20003:F12 12:284 25219 4 RG:1631867:10014:B06 12:291 25305 4 M00056707D:D05 12:377 25309 4 M00056709B:D03 12:381 25332 4 M00055583C:B07 1:55 25337 4 M00056301D:A04 1:60 25393 2 I:2606813:04A02:B12 12:339 25430 2 I:1931371:02B02:D12 12:376

TABLE 9 Chro- mo- Sample Name or Gene some Map CID Clone Name Function Class Pathway GeneAssignment Symbol Num Position 1 I:1222317:15A02:C02 Unknown Ca++ Homo sapiens S100 S100A 1 1q12-q22 binding calcium-binding protein A4 (calcium protein, calvasculin, metastasin, murine placental homolog) (S100A4) mRNA > :: gb|M80563|HUMCAPL Human CAPL protein mRNA, complete cds. 2 I:1227385:14B01:G05 Signal kinase EphB3 [Homo sapiens] EPHB3 3 3q21 Transduction 2 RG:32281:10004:G05 Signal kinase EphB3 [Homo sapiens] EPHB3 3 3q21 Transduction 2 RG:41097:10005:B10 Signal kinase EphB3 [Homo sapiens] EPHB3 3 3q21 Transduction 3 I:1297179:05A02:F02 Metabolism dehydrogenase folate methylenetetrahydrofolate MTHFD1 14 14q24 pathway dehydrogenase (NADP+ dependent), methenyltetrahydrofolate cyclohydrolase, formyltetrahydrofolate synthetase 4 I:1298021:05A01:G10 Cell Cycle pseudouridine rRNA dyskeratosis congenital, DKC1 X Xq28 (psi) processing dyskerin synthase 5 I:1358285:04A02:F11 Signal kinase AXL receptor tyrosine AXL 19 19q13.1 Transduction kinase 5 M00022180D:E11 Signal kinase AXL receptor tyrosine AXL 19 19q13.1 Transduction kinase 6 I:1384823:01B02:F08 Cell Cycle CDC28 CDC28 protein kinase 2 CKS2 9 9q22 subunit 7 I:1395918:04A01:G10 Cytoskeleton GTPase Arg/Abl-interacting ARGBP2 4 4 protein ArgBP2 8 I:1402615:09A02:E03 Cell Cycle ubiquitination Fn14 for type I LOC51330 16 16 transmenmbrane protein 9 I:1421929:05A01:D02 Adhesion cadherin cadherin 3, P-cadherin CDH3 16 16q22 (placental) 10 I:1431819:14B01:D05 GTPase nucleolar P130 10 phosphoprotein p130 11 I:1443877:03B02:B08 Protein proteasome 26S proteasome- POH1 2 2 Degradation subunit associated pad1 homolog 12 I:1450639:03B02:E09 microtubule- caltractin (20 kD CALT X Xq28 organizing calcium-binding protein) 13 I:1480159:06B02:E03 Unknown protease kallikrein 6 (neurosin, KLK6 19 19q13.3 zyme) 14 I:1509602:04A01:A11 Metabolism lipoxygenase arachdonic arachidonate 5- ALOX5 10 10q11.2 metab- lipoxygenase olism 15 I:1516301:05B01:C10 Transcription transcription forkhead box M1 FOXM1 12 12p13 factor 16 I:1600586:05B02:F04 RNA spliceosome splicing factor 3b, SF3B3 splicing subunit 3, 130 kD 17 I:1609538:06A02:F04 Mito- translocase translocase of outer TOM34 20 20 chondrial mitochondrial 20 membrane 34 18 I:1613615:03B01:D10 Signal secreted bone morphogenetic BMP4 14 14q22-q23 Transduction protein 4 19 I:1630804:06A02:F10 Metabolism iron Friedreich ataxia FRDA 9 9q13-q21.1 homeostasis 20 I:1633286:06A02:E04 Unknown membrane transmembrane 4 TM4SF4 3 3 superfamily member 4 21 I:1666080:07B02:D04 Unknown novel 22 I:1699587:06A02:F11 Unknown protease matrix MMP7 11 11q21-q22 metalloproteinase 7 (matrilysin, uterine) 23 I:1702266:02B01:D09 Metabolism carboxylate amino pyrroline-5-carboxylate PYCR1 17 17 reductase acid reductase 1 synthesis 24 I:1712592:04A01:E03 insulin induced gene 1 INSIG1 7 7q36 25 I:1723834:01A01:C02 cell cycle transcription minichromosome MCM2 3 3q21 factor maintenance deficient (S. cerevisiae) 2 (mitotin) 26 I:1743234:16B01:D09 Novel secreted 27 I:1749417:04A02:D10 Unknown protease cathepsin H CTSH 15 15q24-q25 28 I:1749883:05B01:D04 Metabolism kinase pyridoxal (pyridoxine, PDXK 21 21q22.3 vitamin B6) kinase 29 I:1750782:02A01:A08 Unknown novel KIAA0007 protein KIAA0007 2 2 30 I:1758241:15B02:G04 Cell Cycle CDC28 CDC28 protein kinase 1 CKS1 8 8q21 kinase 30 M00056227B:G06 Cell Cycle CDC28 CDC28 protein kinase 1 CKS1 8 8q21 kinase 31 I:1809385:02A02:G04 integrin- integrin beta 3 binding ITGB3BP 1 1 binding protein (beta3- pathway endonexin) [Homo sapiens] 32 I:1810640:01A02:D06 Adhesion kinase EphA1 EPHA1 7 7q32-q36 33 I:1817434:02B01:C02 Nucleotide transketolase transketolase TKT 3 3p14.3 Biosynthesis (Wernicke-Korsakoff syndrome) 34 I:1833191:14A01:G05 Unknown dedicator of cytokinesis 3 DOCK3 3 3 35 I:1854245:02B02:E10 Unknown kinase KIAA0173 gene KIAA0173 2 2 product [Homo sapiens] 36 I:1854558:03A01:C11 Metabolism glycosylation fucosyltransferase 1 FUT1 19 19q13.3 (galactoside 2-alpha-L- fucosyltransferase, Bombay phenotype included) 37 I:1857563:05B02:D01 transcription 6-pyruvoyl- PCBD 10 10q22 factor tetrahydropterin synthase/dimerization cofactor of hepatocyte nuclear factor 1 alpha (TCF1) 38 I:1920522:15B02:F02 Cell Cycle D123 gene product D123 39 I:1920650:16A01:B01 Ca++ annexin A3 ANXA3 4 4q13-q22 signal 41 I:1923490:18B01:H08 Unknown phosphatase hypothetical protein LOC51235 1 1 41 M00022742A:F08 Unknown phosphatase hypothetical protein LOC51235 1 1 42 I:1923769:16B01:F01 Unknown unknown hypothetical protein, HSA272196 17 17q11.2 clone 2746033 43 I:1926006:15A01:F09 DNA mismatch mutS (E. coli) homolog 6 MSH6 2 2p16 Repair repair 44 I:1931371:02B02:D12 Unknown microtubule- KIAA0097 gene KIAA0097 11 11 organizing product 45 I:1960722:13B02:D11 Chaperone HSP90 tumor necrosis factor LOC51721 16 16 type 1 receptor associated protein [Homo sapiens] 46 I:1963753:18B01:E07 Trafficking membrane transporter 47 I:1965257:18B02:B04 Unknown novel 48 I:1967543:16B02:F06 Novel secreted 13 13 49 I:1968921:15A02:D06 Adhesion cell surface immunoglobulin ISLR 15 15q23-q24 superfamily containing leucine-rich repea 50 I:1969044:18B01:E12 Unknown kinase 51 I:1981218:16B02:H01 Unknown transmembrane integral type I protein P24B 15 15q24-q25 53 I:1996180:19B01:C11 Signal GTP Transduction effector 54 I:2054678:19A01:F10 Unknown Ca++ 1 1 binding 55 I:2055926:14A01:F11 Unknown kinase thymidine kinase 1, TK1 17 17q23.2-q25.3 soluble 56 I:2056395:13A02:B07 Adhesion fasciclin transforming growth TGFBI 5 5q31 factor, beta-induced, 68 kD 58 I:2060725:13A01:G10 Ca++ calcyclin binding CACYBP 1 1q24-q25 signal protein [Homo sapiens] 59 I:2079906:01A02:A06 DNA replication Replication factor 60 I:2152363:04A02:A08 Unknown kinase non-metastatic cells 1, NME1 17 17q21.3 protein (NM23A) expressed in 63 I:2239819:04A02:B11 Unknown protease dipeptidase 1 (renal) DPEP1 16 16q24.3 64 I:2359588:18A01:F03 Unknown unknown 65 I:2458926:03B01:C07 Unknown novel KIAA0101 gene KIAA0101 15 15 product [Homo sapiens] 65 M00055423A:C07 Unknown novel KIAA0101 gene KIAA0101 15 15 product [Homo sapiens] 66 I:2483109:05A01:A06 Unknown kinase chromosome 1 open C1ORF2 1 1q21 reading frame 2 67 I:2499479:05A01:D06 Transcription transcription factor NRF NRF 68 I:2499976:01B02:E09 transmembrane 70 I:2606813:04A02:B12 Chaperone isomerase peptidylprolyl PPIE 1 1p32 isomerase E (cyclophilin E) 71 I:2615513:04B01:D09 antizyme polyamine antizyme inhibitor LOC51582 inhibitor synthesis [Homo sapiens] 74 I:2675481:05A01:G06 Mito- protease ClpP (caseinolytic CLPP 19 19 chondrial protease, ATP- dependent, proteolytic subunit, E. coli) homolog 75 I:2759046:19B02:C05 Unknown membrane tetraspan 5 TSPAN-5 4 4 76 I:2825369:07A02:F09 Metabolism transferase serine phosphoserine PSA 9 9 bio- aminotransferase synthesis 77 I:2840195:01B02:G11 Nucleotide kinase adenosine kinase ADK 10 10cen-q24 Biosynthesis 78 I:2902903:12A02:F02 Adhesion transmembrane interferon induced IFITM1 11 11 transmembrane protein 1 (9-27) 79 I:2914605:04B01:G06 Unknown unknown KIAA0170 gene KIAA0170 6 6p21.3 product [Homo sapiens] 80 I:2914719:04B02:B05 nuclear RAE1 (RNA export 1, RAE1 20 20 export S. pombe) homolog 81 I:3229778:02B01:B07 Adhesion integrin integrin, alpha 2 ITGA2 5 5q23-31 (CD49B, alpha 2 subunit of VLA-2 receptor) 83 I:3518380:16A01:B07 Metabolism sterol cholesterol 7-dehydrocholesterol DHCR7 11 11q13.2-q13.5 reductase bio- reductase synthesis 85 I:4072558:12B01:A07 Translation initiation factor 87 I:549299:17B02:F06 Novel KIAA0784 protein KIAA0784 20 20q13.13-q13.2 88 I:605019:13B02:D03 Unknown transferase catechol-O- COMT 22 22q11.21 methyltransferase 89 I:620494:16A01:C10 Unknown proteasome proteasome (prosome, PSMB7 9 9q34.11-q34.12 subunit macropain) subunit, beta type, 7 90 I:659143:16B01:E06 Unknown novel 91 I:750899:16A01:D04 Unknown phosphatase protein tyrosine PTPRN 2 2q35-q36.1 phosphatase, receptor type, N 92 I:763607:16A01:E09 Unknown unknown tumor protein D52-like 1 TPD52L1 6 6q22-q23 93 I:901317:16A01:G01 Unknown proteasome proteasome (prosome, PSMB4 1 1q21 subunit macropain) subunit, beta type, 4 94 I:956077:14B01:H04 DNA GTPase nudix (nucleoside NUDT1 7 7p22 Repair diphosphate linked moiety X)-type motif 1 95 I:970933:14B01:D03 Novel secreted FOXJ2 forkhead factor LOC55810 96 I:986558:18A01:C09 Unknown unknown 3 98 I:998612:14B02:G06 Metabolism dehydrogenase 3-phosphoglycerate PHGDH 1 1p11.1-13.1 dehydrogenase 100 M00001341B:A11 Cell Cycle kinase KIAA0175 gene KIAA0175 9 9 product [Homo sapiens] 101 M00001349A:C11 Adhesion kinase discoidin domain DDR1 6 6p21.3 receptor family, member 1 102 M00001351C:E02 Unknown unknown cathepsin C CTSC 11 11q14.1-q14.3 103 M00001374A:A06 Unknown desaturase stearoyl-CoA SCD 10 10 desaturase 104 M00001393D:F01 Metabolism dehydrogenase lactate dehydrogenase B LDHB 12 12p12.2-p12.1 105 M00001402B:C12 Cell Cycle kinase cyclin-dependent CDK4 12 12q14 kinase 4 106 M00001402C:B01 Unknown unknown catenin (cadherin- CTNNAL1 9 9q31.2 associated protein), alpha-like 1 109 M00001489B:G04 HSPC003 protein HSPC003 [Homo sapiens] 110 M00001496A:G03 Transcription transcription v-myb avian MYBL2 20 20q13.1 factor myeloblastosis viral oncogene homolog-like 2 111 M00001558C:B06 Unknown novel hypothetical protein HSPC130 20 20 112 M00001600C:B11 helicase DEAD-box protein ABS 5 5 abstrakt [Homo sapiens] 113 M00001675B:G05 Novel GTPase KIAA0712 gene KIAA0712 11 11 product [Homo sapiens] 114 M00003814C:C11 Unknown novel KIAA0116 protein KIAA0116 3 3 115 M00003852B:C01 Signal cytokine prostate differentiation PLAB 19 19p13.1-13.2 Transduction factor 116 M00003853B:G11 Unknown novel 20 20 117 M00003961B:H05 Unknown kinase EphB4 EPHB4 7 7 118 M00004031B:D12 Unknown secreted 118 M00057112B:E11 Unknown secreted 120 M00004229C:B06 Unknown protease cathepsin Z CTSZ 20 20q13 121 M00005360A:A07 Novel calcitonin EGF-like-domain, EGFL2 1 1 receptor multiple 2 122 M00005438D:D06 Unknown protease beta-site APP-cleaving BACE2 21 21q22.3 enzyme 2 123 M00006883D:H12 Unknown novel 124 M00007935D:A05 Unknown novel 7 7 125 M00007965C:G08 Unknown unknown 126 M00007985A:B08 Unknown novel 1 1 127 M00007985B:A03 sigma sigma receptor SR-BP1 9 9 receptor (SR31747 binding protein 1) 128 M00007987D:D04 Novel secreted KIAA0179 KIAA0179 21 21q22.3 129 M00008049B:A12 RNA non-Pou domain- NONO X Xq13.1 Splicing containing octamer (ATGCAAAT) binding protein [Homo sapiens] 129 RG:25258:10004:D09 RNA non-Pou domain- NONO X Xq13.1 Splicing containing octamer (ATGCAAAT) binding protein [Homo sapiens] 130 M00008099D:A05 Unknown secreted 20 20 131 M00021828C:F04 Unknown kinase dual-specificity DYRK4 12 12 tyrosine-(Y)- phosphorylation regulated kinase 4 132 M00021956B:A09 Transcription transcription ets variant gene 4 (E1A ETV4 17 17q21 factor enhancer-binding protein, E1AF) 133 M00022009A:A12 Unknown unknown pleckstrin homology- PHLDA1 12 12q15 like domain, family A, member 1 134 M00022081D:G02 Unknown kinase Ste20-related KIAA0204 10 10 serine/threonine kinase [Homo sapiens] 135 M00022158D:C11 Adhesion laminin laminin, beta 3 (nicein LAMB3 1 1q32 (125 kD), kalinin (140 kD), BM600 (125 kD)) 136 M00022168B:F02 Unknown deaminase hypothetical protein FLJ10540 FLJ10540 137 M00022215C:A10 Unknown unknown 138 M00023283C:C06 Unknown novel hypothetical protein HN1L 16 16 similar to mouse HN1 (Hematological and Neurological expressed sequence 1) 139 M00023363C:A04 Unknown protease kallikrein 11 KLK11 19 19q13.3-q13.4 140 M00023371A:G03 Cell Cycle retinoblastoma-binding RBBP8 18 18q11.2 protein 8 141 M00023431B:A01 Ribosomal small 6 6q14.3-16.2 Biogenesis nucleolar RNA 142 M00026888A:A03 Unknown novel 143 M00026900D:F02 Metabolism transferase sulfotransferase family SULT2B1 19 19q13.3 2B, member 1 144 M00026903D:D11 Metabolism kinase galactokinase 1 GALK1 17 17q24 145 M00027066B:E09 Unknown unknown 146 M00032537B:F11 Unknown transmembrane 147 M00042439D:C11 Cell Cycle ubiquitin ubiquitin carrier protein UBCH10 20 20 carrier E2-C 148 M00042704D:D09 Unknown novel 149 M00042756A:H02 Cell Cycle SET translocation SET 9 9q34 (myeloid leukemia- associated) 150 M00042770D:G04 hypothetical protein MAC30 17 17 151 M00042818A:D05 Unknown integrase 151 M00054520A:D04 Unknown integrase 152 M00054500D:C08 Unknown proteasome proteasome (prosome, PSMA7 subunit macropain) subunit, alpha type, 7 153 M00054538C:C01 Autophagy Apg12 (autophagy 12, APG12L 5 5q21-q22 S. cerevisiae)-like 154 M00054639D:F05 GTP nucleocyto karyopherin (importin) KPNB3 binding plasmic beta 3 transport? 155 M00054647A:A09 Metabolism glyoxalase glyoxalase I GLO1 6 6p21.3-p21.1 156 M00054650D:E04 Ribosomal RNA, U22 small RNU22 11 11q13 Biogenesis nucleolar 157 M00054742C:B12 Unknown cytokine macrophage migration MIF 22 22q11.23 inhibitory factor (glycosylation- inhibiting factor) 158 M00054769A:E05 Translation ribosomal ribosomal protein S3A RPS3A 4 4q31.2-q31.3 protein 159 M00054777D:E09 Unknown secreted carcinoembryonic CEACAM6 19 19q13.2 antigen-related cell adhesion molecule 6 (non-specific cross reacting antigen) 160 M00054806B:G03 Unknown snRNA 161 M00054893C:D03 Unknown novel putative nucleotide E2IG3 binding protein, estradiol-induced [Homo sapiens] 162 M00054971D:D07 Unknown novel 20 20q13.2-13.2 163 M00055135A:B06 Unknown unknown hypothetical protein HSPC011 [Homo sapiens] 164 M00055258B:D12 interferon induced IFITM2 11 11 transmembrane protein 2 (1-8D) 165 M00055406C:D03 Unknown kinase CDC-like kinase 1 CLK1 2 2q33 166 M00055435B:A12 Apoptosis unknown over-expressed breast OBTP tumor protein 167 M00055583C:B07 Novel secreted hypothetical protein LOC51316 [Homo sapiens] 169 M00055873C:B06 Unknown protease secretory leukocyte SLPI inhibitor protease inhibitor (antileukoproteinase) 170 M00056250C:B02 transmembrane pituitary tumor- PTTG1 5 5q35.1 transforming 1 171 M00056301D:A04 Unknown unknown 172 M00056308A:F02 sulfate/ down-regulated in DRA 7 7q31 oxalate adenoma Trans- porter? 173 M00056350B:B03 Cytoskeleton Ca++ S100 calcium-binding S100A11 1 1q21 binding protein A11 (calgizzarin) 174 M00056423A:B06 Unknown novel hypothetical protein HSPC148 11 11 [Homo sapiens] 175 M00056478D:B07 Unknown novel clone HQ0310 LOC51203 15 15 PRO0310p1 [Homo sapiens] 176 M00056483D:G07 Unknown protease kallikrein 10 KLK10 19 19q13 176 M00057046A:G09 Unknown protease kallikrein 10 KLK10 19 19q13 177 M00056500C:A07 nascent-polypeptide- NACA 12 12q23-q24.1 associated complex alpha polypeptide 178 M00056533D:G07 Unknown secreted DKFZP434G032 DKFZP434G032 17 17 protein [Homo sapiens] 179 M00056534C:E08 Signal secreted amphiregulin AREG 4 4q13-q21 Transduction (schwannoma-derived growth factor) 180 M00056585B:F04 Unknown hydrolase gamma-glutamyl GGH hydrolase (conjugase, folylpolygammaglutamyl hydrolase) 181 M00056617D:F07 Unknown novel 182 M00056619A:H02 Cytoskeleton plastin plastin 3 (T isoform) PLS3 X X 183 M00056622B:F12 DNA topoisomerase topoisomerase (DNA) TOP2A 17 17q21-q22 Replication II alpha (170 kD) 184 M00056632B:H10 ATP/GTP chromosome 20 open C20ORF1 20 20q11.2 binding reading frame 1 185 M00056645C:D11 Metabolism peroxidase oxidative glutathione peroxidase 1 GPX1 3 3p21.3 metab- olism 186 M00056646B:F07 ribosomal protein L7a RPL7A 9 9q33-q34 187 M00056679B:H03 nucleophosmin NPM1 5 5q35 (nucleolar phosphoprotein B23, numatrin) 188 M00056707D:D05 Unknown novel 189 M00056709B:D03 Unknown novel CGI-138 protein LOC51649 17 17 [Homo sapiens] 190 M00056728C:G02 Cell Cycle MAD2 (mitotic arrest MAD2L1 4 4q27 deficient, yeast, homolog)-like 1 191 M00056732B:E02 Unknown novel LIM domain only 7 LMO7 13 13 192 M00056810A:A02 Novel GTP hypothetical protein PTD004 binding 193 M00056812D:A08 Unknown hydrolase S- AHCY 20 20cen-q13.1 adenosylhomocysteine hydrolase 194 M00056822A:E08 Signal RAS-like RAN, member RAS RAN 6 6p21 Transduction oncogene family 195 M00055209C:B07 Unknown novel 7 7p14-p15 195 M00056908A:H05 Unknown novel 7 7p14-p15 196 M00056918C:F09 Unknown novel hypothetical protein HSPC152 11 11 [Homo sapiens] 197 M00056937C:C10 Cell Cycle Ca++ S100 calcium-binding S100P 4 4p16 binding protein P 198 M00056953B:C09 Unknown proteasome proteasome (prosome, PSME2 14 14q11.2 subunit macropain) activator subunit 2 (PA28 beta) 199 M00056992C:F12 Unknown unknown 200 M00057044D:G03 Unknown unknown 6 6 201 M00057081B:H03 Unknown unknown ribosomal protein L10a RPL10A 202 M00057086D:D08 Unknown unknown RNA binding motif RBM8 1 1q12 protein 8 203 M00057126C:B03 Unknown novel 204 M00057127B:B09 Unknown unknown 205 M00057192B:D02 Unknown unknown 206 M00057231A:G04 Transcription transcription non-metastatic cells 2, NME2 17 17q21.3 factor protein (NM23B) expressed in 206 RG:1651303:10014:E01 Transcription transcription non-metastatic cells 2, NME2 17 17q21.3 factor protein (NM23B) expressed in 207 M00057241C:F03 Translation initiation eukaryotic translation EIF3S6 8 8q22-q23 factor initiation factor 3, subunit 6 (48 kD) 208 RG:110764:10005:H04 kinase protein kinase related PAK4 19 19 to S. cerevisiae STE20, effector for Cdc42Hs 210 RG:1325847:10012:H07 Unknown transmembrane 6 6q23 212 RG:1353123:10013:A06 Cell Cycle phosphatase cyclin-dependent CDKN3 14 14q22 kinase inhibitor 3 (CDK2-associated dual specificity phosphatase) 212 RG:1637619:10014:C02 Cell Cycle phosphatase cyclin-dependent CDKN3 14 14q22 kinase inhibitor 3 (CDK2-associated dual specificity phosphatase) 213 RG:1374447:20004:G01 Unknown novel 214 RG:1461567:10013:E03 Cell Cycle kinase budding uninhibited by BUB1 2 2q14 benzimidazoles 1 (yeast homolog) 215 RG:1525813:10013:F12 Unknown novel 2 2 216 RG:1552386:10013:G04 phosphatase acid phosphatase 1, ACP1 2 2p25 soluble 217 RG:1555877:10013:G07 Metabolism NADPH neutrophil cytosolic NCF4 22 22q13.1 oxidase factor 4 (40 kD), isoform 1 [Homo sapiens] 218 RG:1630930:10014:B05 nucleic kinase deoxythymidylate DTYMK 2 2 acid kinase synthesis 219 RG:1631867:10014:B06 DNA Ku protein dsDNA X-ray repair XRCC5 2 2q35 Repair repair complementing defective repair in Chinese hamster cells 5 (double-strand-break rejoining; Ku autoantigen, 80 kD) 220 RG:1638979:10014:C04 Metabolism GST drug glutathione S- GSTP1 11 11q13 metab- transferase pi olism 221 RG:1645945:10014:D05 proteasome proteasome (prosome, PSMA2 6 6q27 subunit macropain) subunit, alpha type, 2 221 RG:1674393:10014:H02 proteasome proteasome (prosome, PSMA2 6 6q27 subunit macropain) subunit, alpha type, 2 222 RG:166410:10006:F01 Novel kinase 223 RG:1674098:10014:H01 Unknown unknown myristoylated alanine- MACS 6 6q22.2 rich protein kinase C substrate (MARCKS, 80K-L) 224 RG:180296:10006:G03 kinase protein tyrosine kinase PTK2B 8 8p21.1 2 beta 225 RG:1838677:10015:E10 kinase membrane-associated PKMYT1 tyrosine- and threonine-specific cdc2-inhibitory kinase 226 RG:1861510:20001:B03 Unknown novel 227 RG:1895716:10015:G09 Novel kinase 14 14 228 RG:1927470:10015:H08 Metabolism kinase glycolysis phosphoglycerate PGK1 X Xq13 kinase 1 229 RG:1996788:20003:C10 Unknown novel 230 RG:1996901:20003:D01 Unknown novel 231 RG:2002384:20003:E01 Unknown novel 232 RG:2006302:20003:F08 Unknown novel 233 RG:2006592:20003:F12 Unknown novel 12 235 RG:2012168:10016:B05 Metabolism hydrolase phosphoribosyl PPAT 4 4q12 pyrophosphate amidotransferase 236 RG:203031:10007:A09 Unknown kinase serine/threonine kinase STK15 20 20q13.2-q13.3 15 236 RG:781507:10011:E01 Unknown kinase serine/threonine kinase STK15 20 20q13.2-q13.3 15 237 RG:2048081:10016:B08 kinase mitogen-activated MAPK10 protein kinase 10 238 RG:2051667:20003:H05 Unknown novel 1 1 239 RG:2055807:10016:B09 Unknown kinase 20 20p12.2-13 240 RG:208954:10007:B12 kinase Xq25-26.3 241 RG:2097257:10016:C07 Unknown protease serine protease, SPUVE 12 12 umbilical endothelium 242 RG:2097294:10016:C08 Mito- transferase thymi- serine SHMT2 12 12q12-q14 chondrial dylate hydroxymethyltransferase synthase 2 (mitochondrial) metabolic cycle 243 RG:2117694:10016:E01 Unknown kinase serine/threonine kinase STK11 19 19p13.3 11 (Peutz-Jeghers syndrome) 244 RG:241029:10007:D07 Unknown kinase serine/threonine kinase STK12 17 17p13.1 12 245 RG:244132:10007:E01 kinase serum/glucocorticoid SGKL 8 8q12.3-8q13.1 regulated kinase-like 246 RG:244601:10007:E02 Cell Cycle kinase cyclin-dependent CDK5 7 7q36 kinase 5 247 RG:27403:10004:E11 Novel transmembrane 248 RG:278409:10008:B10 Unknown kinase mitogen-activated MAP2K4 17 17p11.2 protein kinase kinase 4 249 RG:29739:10004:F02 Cell Cycle kinase TTK protein kinase TTK 6 6q13-q21 250 RG:301608:10008:D09 kinase serine/threonine- PRP4 protein kinase PRP4 homolog 251 RG:306813:10008:E12 kinase v-ros avian UR2 ROS1 6 6q22 sarcoma virus oncogene homolog 1 252 RG:1635546:10014:B08 Ribosomal nucleolar protein NOP56 20 20 Biogenesis (KKE/D repeat) 252 RG:323425:10008:F11 Ribosomal nucleolar protein NOP56 20 20 Biogenesis (KKE/D repeat) 253 RG:343821:10008:H05 kinase TYRO3 protein TYRO3 15 15q15.1-q21.1 tyrosine kinase 254 RG:35892:10004:H10 kinase activin A receptor, type I ACVR1 2 2q23-q24 255 RG:364972:10009:B06 Unknown novel 19 19 256 RG:376554:10009:B12 Unknown novel 8 8 257 RG:417109:10009:D09 Unknown novel 9 9 258 RG:43296:10005:C03 kinase SFRS protein kinase 2 SRPK2 7 7q22-q31.1 259 RG:432960:10009:E11 Transcription deacetylase retinoblastoma-binding RBBP7 protein 7 260 RG:43534:10005:C04 kinase ribosomal protein S6 RPS6KA1 3 3 kinase, 90 kD, polypeptide 1 261 RG:45623:10005:D09 Unknown novel HSKM-B protein HSKM-B 262 RG:471154:10009:H04 protease tissue inhibitor of TIMP3 22 22q12.3 inhibitor metalloproteinase 3 (Sorsby fundus dystrophy, pseudoinflammatory) 263 RG:487171:10009:H09 Unknown kinase polo (Drosophia)-like PLK kinase 264 RG:526536:10002:A02 kinase solute carrier family 9 SLC9A3R2 16 16p13.3 (sodium/hydrogen exchanger), isoform 3 regulatory factor 2 265 RG:530002:10002:A08 kinase EphA3 EPHA3 3 3p11.2 266 RG:612874:10002:G02 kinase serum-inducible kinase SNK 5 5 267 RG:665547:10010:B04 Unknown novel 2 2 268 RG:665682:10010:B05 Unknown kinase mitogen-activated MAP2K7 protein kinase kinase 7 269 RG:666323:10010:B07 kinase sterile-alpha motif and ZAK 2 2q24.2 leucine zipper containing kinase AZK [Homo sapiens] 270 RG:669110:10010:B12 Novel kinase 271 RG:686594:10010:D03 Cell Cycle kinase KIAA0965 protein KIAA0965 12 12 273 RG:729913:10010:G11 Unknown kinase 14 14 274 RG:740831:10010:H12 kinase v-rafmurine sarcoma ARAF1 X Xp11.4-p11.2 3611 viral oncogene homolog 1 276 RG:742764:10011:A06 RNA splicing factor, SFRS3 splicing arginine/serine-rich 3 277 RG:781028:10011:D08 kinase mitogen-activated MAP4K3 protein kinase kinase kinase kinase 3 278 RG:785368:10011:E11 Novel kinase PDZ-binding kinase; T- TOPK 8 8p21-p12 cell originated protein kinase 278 RG:785846:10011:F02 Novel kinase PDZ-binding kinase; T- TOPK 8 8p21-p12 cell originated protein kinase 280 RG:985973:10012:B09 Unknown kinase v-akt murine thymoma AKT3 1 1q43-q44 viral oncogene homolog 3 (protein kinase B, gamma) 291 M00022140A:E11 Chaperone HSP90 heat shock 90 kD HSPCB 6 6p12 protein 1, beta M00054510D:F09 RG:742775:10011:A07 RG:759927:10011:C09 RG:773612:10011:D06 RG:813679:10011:H03

The differential expression assay was performed by mixing equal amounts of probes from tumor cells and normal cells of the same patient. The arrays were prehybridized by incubation for about 2 hrs at 60° C. in 5×SSC/0.2% SDS/1 mM EDTA, and then washed three times in water and twice in isopropanol. Following prehybridization of the array, the probe mixture was then hybridized to the array under conditions of high stringency (overnight at 42° C. in 50% formamide, 5×SSC, and 0.2% SDS. After hybridization, the array was washed at 55° C. three times as follows: 1) first wash in 1×SSC/0.2% SDS; 2) second wash in 0.1×SSC/0.2% SDS; and 3) third wash in 0.1×SSC.

The arrays were then scanned for green and red fluorescence using a Molecular Dynamics Generation III dual color laser-scanner/detector. The images were processed using BioDiscovery Autogene software, and the data from each scan set normalized to provide for a ratio of expression relative to normal. Data from the microarray experiments was analyzed according to the algorithms described in U.S. application Ser. No. 60/252,358, filed Nov. 20, 2000, by E. J. Moler, M. A. Boyle, and F. M. Randazzo, and entitled “Precision and accuracy in cDNA microarray data,” which application is specifically incorporated herein by reference.

The experiment was repeated, this time labeling the two probes with the opposite color in order to perform the assay in both “color directions.” Each experiment was sometimes repeated with two more slides (one in each color direction). The level fluorescence for each sequence on the array expressed as a ratio of the geometric mean of 8 replicate spots/genes from the four arrays or 4 replicate spots/gene from 2 arrays or some other permutation. The data were normalized using the spiked positive controls present in each duplicated area, and the precision of this normalization was included in the final determination of the significance of each differential. The fluorescent intensity of each spot was also compared to the negative controls in each duplicated area to determine which spots have detected significant expression levels in each sample.

A statistical analysis of the fluorescent intensities was applied to each set of duplicate spots to assess the precision and significance of each differential measurement, resulting in a p-value testing the null hypothesis that there is no differential in the expression level between the tumor and normal samples of each patient. During initial analysis of the microarrays, the hypothesis was accepted if p>10⁻³, and the differential ratio was set to 1.000 for those spots. All other spots have a significant difference in expression between the tumor and normal sample. If the tumor sample has detectable expression and the normal does not, the ratio is truncated at 1000 since the value for expression in the normal sample would be zero, and the ratio would not be a mathematically useful value (e.g., infinity). If the normal sample has detectable expression and the tumor does not, the ratio is truncated to 0.001, since the value for expression in the tumor sample would be zero and the ratio would not be a mathematically useful value. These latter two situations are referred to herein as “on/off.” Database tables were populated using a 95% confidence level (p>0.05).

Table 6 (incorpororated by reference to a compact disk) provides the results for gene products differentially expressed in the colon tumor samples relative to normal tissue samples. Table 6 includes: 1) the SEQ ID NO; 2) the CID or candidate identification number; 3) the spot identification number (“SpotID”); 4) the percentage of patients tested in which expression levels of the gene was at least 2-fold greater in cancerous tissue than in matched normal tissue (“>=2×”); 5) the percentage of patients tested in which expression levels of the gene was at least 2.5-fold greater in cancerous tissue than in matched normal tissue (“>=2.5×”); 6) the percentage of patients tested in which expression levels of the gene was at least 5-fold greater in cancerous tissue than in matched normal cells (“>=5×”); 7) the percentage of patients tested in which expression levels of the gene was less than or equal to ½ of the expression level in matched normal cells (“<=half×”); and 8) the number of patients tested for each sequence. Table 6 also includes the results from each patient, identified by the patient ID number (e.g., 15Ratio). This data represents the ratio of differential expression for the samples tested from that particular patient's tissues (e.g., “15Ratio” is the ratio from the tissue samples of patient ID no. 15). The ratios of differential expression is expressed as a normalized hybridization signal associated with the tumor probe divided by the normalized hybridization signal with the normal probe. Thus, a ratio greater than 1 indicates that the gene product is increased in expression in cancerous cells relative to normal cells, while a ratio of less than 1 indicates the opposite.

These data provide evidence that the genes represented by the polynucleotides having the indicated sequences are differentially expressed in colon cancer.

Example 3 Antisense Regulation of Gene Expression

The expression of the differentially expressed genes represented by the polynucleotides in the cancerous cells was analyzed using antisense knockout technology to confirm the role and function of the gene product in tumorigenesis, e.g., in promoting a metastatic phenotype.

A number of different oligonucleotides complementary to the mRNA generated by the differentially expressed genes identified herein were designed as potential antisense oligonucleotides, and tested for their ability to suppress expression of the genes. Sets of antisense oligomers specific to each candidate target were designed using the sequences of the polynucleotides corresponding to a differentially expressed gene and the software program HYBsimulator Version 4 (available for Windows 95/Windows NT or for Power Macintosh, RNAture, Inc. 1003 Health Sciences Road, West, Irvine, Calif. 92612 USA). Factors considered when designing antisense oligonucleotides include: 1) the secondary structure of oligonucleotides; 2) the secondary structure of the target gene; 3) the specificity with no or minimum cross-hybridization to other expressed genes; 4) stability; 5) length and 6) terminal GC content. The antisense oligonucleotide is designed to so that it will hybridize to its target sequence under conditions of high stringency at physiological temperatures (e.g., an optimal temperature for the cells in culture to provide for hybridization in the cell, e.g., about 37° C.), but with minimal formation of homodimers.

Using the sets of oligomers and the HYBsimulator program, three to ten antisense oligonucleotides and their reverse controls were designed and synthesized for each candidate mRNA transcript, which transcript was obtained from the gene corresponding to the target polynucleotide sequence of interest. Once synthesized and quantitated, the oligomers were screened for efficiency of a transcript knock-out in a panel of cancer cell lines. The efficiency of the knock-out was determined by analyzing mRNA levels using lightcycler quantification. The oligomers that resulted in the highest level of transcript knock-out, wherein the level was at least about 50%, preferably about 80-90%, up to 95% or more up to undetectable message, were selected for use in a cell-based proliferation assay, an anchorage independent growth assay, and an apoptosis assay.

The ability of each designed antisense oligonucleotide to inhibit gene expression was tested through transfection into SW620 colon colorectal carcinoma cells. For each transfection mixture, a carrier molecule, preferably a lipitoid or cholesteroid, was prepared to a working concentration of 0.5 mM in water, sonicated to yield a uniform solution, and filtered through a 0.45 μm PVDF membrane. The antisense or control oligonucleotide was then prepared to a working concentration of 100 μM in sterile Millipore water. The oligonucleotide was further diluted in OptiMEM™ (Gibco/BRL), in a microfuge tube, to 2 μM, or approximately 20 μg oligo/ml of OptiMEM™. In a separate microfuge tube, lipitoid or cholesteroid, typically in the amount of about 1.5-2 nmol lipitoid/pg antisense oligonucleotide, was diluted into the same volume of OptiMEMm used to dilute the oligonucleotide. The diluted antisense oligonucleotide was immediately added to the diluted lipitoid and mixed by pipetting up and down. Oligonucleotide was added to the cells to a final concentration of 30 nM.

The level of target mRNA that corresponds to a target gene of interest in the transfected cells was quantitated in the cancer cell lines using the Roche LightCycler™ real-time PCR machine. Values for the target mRNA were normalized versus an internal control (e.g., beta-actin). For each 20 μl reaction, extracted RNA (generally 0.2-1 μg total) was placed into a sterile 0.5 or 1.5 ml microcentrifuge tube, and water was added to a total volume of 12.5 μl. To each tube was added 7.5 μl of a buffer/enzyme mixture, prepared by mixing (in the order listed) 2.5 μl H₂O, 2.0 μl 10× reaction buffer, 10 μl oligo dT (20 pmol), 1.0 μl dNTP mix (10 mM each), 0.5 μl RNAsin® (20 u) (Ambion, Inc., Hialeah, Fla.), and 0.5 μl MMLV reverse transcriptase (50 u) (Ambion, Inc.). The contents were mixed by pipetting up and down, and the reaction mixture was incubated at 42° C. for 1 hour. The contents of each tube were centrifuged prior to amplification.

An amplification mixture was prepared by mixing in the following order: 1× PCR buffer II, 3 mM MgCl₂, 140 μM each dNTP, 0.175 pmol each oligo, 1:50,000 dil of SYBR® Green, 0.25 mg/ml BSA, 1 unit Taq polymerase, and H₂O to 20 μl. (PCR buffer II is available in 10× concentration from Perkin-Elmer, Norwalk, Conn.). In 1× concentration it contains 10 mM Tris pH 8.3 and 50 mM KCl. SYBR® Green (Molecular Probes, Eugene, Oreg.) is a dye which fluoresces when bound to double stranded DNA. As double stranded PCR product is produced during amplification, the fluorescence from SYBR® Green increases. To each 20 μl aliquot of amplification mixture 2 μl of template RT was added, and amplification was carried out according to standard protocols.

The results of the antisense assays are provided in Table 7 (inserted before the claims). The results are expressed as the percent decrease in expression of the corresponding gene product relative to non-transfected cells, vehicle-only transfected (mock-transfected) cells, or cells transfected with reverse control oligonucleotides. Table 7 includes: 1) the SEQ ID NO; 2) the CID; 3) the “Gene Assignment” which refers to the gene to which the sequence has the greatest homology or identity; 4) the “Gene Symbol ”, 5) GenBank gene name; and 6) the percent decrease in expression of the gene relative to control cells (“mRNA KO”). TABLE 7 SEQ ID Gene GenBank mRNA NO CID GeneAssignment Symbol Gene Name KO  4 1 Homo sapiens S100 calcium-binding protein S100A S100A4 >80% A4 (calcium protein, calvasculin, metastasin, murine placental homolog) (S100A4) mRNA > :: gb|M80563|HUMCAPL Human CAPL protein mRNA, complete cds.  9 6 CDC28 protein kinase 2 CKS2 CKS2 01/ >80% 11  11 8 Fn14 for type I transmenmbrane protein LOC51330 Fn14 >90%  12 9 cadherin 3, P-cadherin (placental) CDH3 CADHERIN-P >90%  16 13 kallikrein 6 (neurosin, zyme) KLK6 proteaseM >80%  17 14 arachidonate 5-lipoxygenase ALOX5 ALOX5 >80%  22 18 bone morphogenetic protein 4 BMP4 BMP4 >90%  25 21 GSTHOM >90%  32 27 cathepsin H CTSH CATH-H >90%  38 33 transketolase (Wernicke-Korsakoff TKT TRANSKETOLASE >90% syndrome)  41 36 fucosyltransferase 1 (galactoside 2-alpha-L- FUT1 FUT1 >90% fucosyltransferase, Bombay phenotype included)  42 37 6-pyruvoyl-tetrahydropterin PCBD hDohc >95% synthase/dimerization cofactor of hepatocyte nuclear factor 1 alpha (TCF1)  54 50 THC271862 >70%  56 53 hECT2 >80%  63 63 dipeptidase 1 (renal) DPEP1 DPP >80%  71 74 ClpP (caseinolytic protease, ATP-dependent, CLPP CLPP >80% proteolytic subunit, E. coli) homolog  77 75 tetraspan 5 TSPAN-5 NET-4 >90%  78 76 phosphoserine aminotransferase PSA serAT >90%  87 121 EGF-like-domain, multiple 2 EGFL2 EGFL2 >70% 100 127 sigma receptor (SR31747 binding protein 1) SR-BP1 SR-BP1 >90% 113 92 tumor protein D52-like 1 TPD52L1 hD53 >80% 141 143 sulfotransferase family 2B, member 1 SULT2B1 SULT2B1 >80% 147 166 over-expressed breast tumor protein OBTP HUMTUM >90% 165 179 amphiregulin (schwannoma-derived growth AREG AREG >90% factor) 180 193 S-adenosylhomocysteine hydrolase AHCY HUMAHCY2 >70% 183 196 hypothetical protein [Homo sapiens] HSPC152 c719 >80% 208 155 glyoxalase I GLO1 GLO1 >90% 213 160 c374641 >80% 214 161 putative nucleotide binding protein, E2IG3 c454001 >80% estradiol-induced [Homo sapiens] 218 164 interferon induced transmembrane protein 2 IFITM2 1-8U >90% (1-8D) 233 263 polo (Drosophia)-like kinase PLK PLK1 >90% 236 266 serum-inducible kinase SNK SNK >80% 239 269 sterile-alpha motif and leucine zipper ZAK AZK >70% containing kinase AZK [Homo sapiens] 242 273 AA399596 >70% 253 280 v-akt murine thymoma viral oncogene AKT3 AKT3 >90% homolog 3 (protein kinase B, gamma) 276 227 ITAK1 >90% 279 239 AI335279 >90% 285 242 serine hydroxymethyltransferase 2 SHMT2 SHMT2 >90% (mitochondrial) 294 245 serum/glucocorticoid regulated kinase-like SGKL SGKL >90% 295 248 mitogen-activated protein kinase kinase 4 MAP2K4 MKK4 >80% 300 249 TTK protein kinase TTK hTTK >90% 123, 103 stearoyl-CoA desaturase SCD SCD >90% 124 130, 115 prostate differentiation factor PLAB PLAB >80% 228 162, 176 kallikrein 10 KLK10 NES1 >80% 193 182, 195 c1665 >80% 217 247, 236 serine/threonine kinase 15 STK15 hARK2 >80% 290 257, 212 cyclin-dependent kinase inhibitor 3 (CDK2- CDKN3 KAP >85% 268 associated dual specificity phosphatase) 31, 170 pituitary tumor-transforming 1 PTTG1 PTTG1 >90% 151 35, 30 CDC28 protein kinase 1 CKS1 CKS1 >80% 150 5, 2 EphB3 [Homo sapiens] EPHB3 EPHB3 >90% 298, 301 65, 65 KIAA0101 gene product [Homo sapiens] KIAA0101 KIAA0101 >80% 220 73, 100 KIAA0175 gene product [Homo sapiens] KIAA0175 KIAA0175 >90% 116 75, 106 catenin (cadherin-associated protein), alpha- CTNNAL1 RTA000001 >90% 131, like 1 79AF.k.22.1 134 8, 106 5 AXL receptor tyrosine kinase AXL >95% 88, 118 c3376 >80% 196

Example 4 Effect of Expression on Proliferation

The effect of gene expression on the inhibition of cell proliferation was assessed in metastatic breast cancer cell lines (MDA-MB-231 (“231”)), SW620 colon colorectal carcinoma cells, or SKOV3 cells (a human ovarian carcinoma cell line).

Cells were plated to approximately 60-80% confluency in 96-well dishes. Antisense or reverse control oligonucleotide was diluted to 2 μM in OptiMEM™ and added to OptiMEM™ into which the delivery vehicle, lipitoid 116-6 in the case of SW620 cells or 1:1 lipitoid 1:cholesteroid 1 in the case of MDA-MB-231 cells, had been diluted. The oligo/delivery vehicle mixture was then further diluted into medium with serum on the cells. The final concentration of oligonucleotide for all experiments was 300 nM, and the final ratio of oligo to delivery vehicle for all experiments was 1.5 nmol lipitoid/μg oligonucleotide.

Antisense oligonucleotides were prepared as described above (see Example 3). Cells were transfected overnight at 37° C. and the transfection mixture was replaced with fresh medium the next morning. Transfection was carried out as described above in Example 3.

The results of the antisense experiments are shown in Table 8 (inserted before the claims, column labeled “Proliferation”). Those antisense oligonucleotides that resulted in decreased proliferation in SW620 colorectal carcinoma cells are indicated by “Inhib in” and “weak effect in”, with the cell type following. Those antisense oligonucleotides that resulted in inhibition of proliferation of SW620 cells indicates that the corresponding gene plays a role in production or maintenance of the cancerous phenotype in cancerous colon cells. Those antisense oligonucleotides that inhibited proliferation in SKOV3 cells represent genes that play a role in production or maintenance of the cancerous phenotype in cancerous breast cells. Those antisense oligonucleotides that resulted in inhibition of proliferation of MDA-MB-231 cells indicates that the corresponding gene plays a role in production or maintenance of the cancerous phenotype in cancerous ovarian cells. TABLE 8 SEQ ID Gene mRNA NO CID GeneAssignment Symbol Gene KO Proliferation Softagar  4 1 Homo sapiens S100 S100A S100A4 >80% Inhib in weak calcium-binding protein SW620 inhibition A4 (calcium protein, calvasculin, metastasin, murine placental homolog) (S100A4) mRNA > :: gb|M80563|HUMCAPL Human CAPL protein mRNA, complete cds.  11 8 Fn14 for type I LOC51330 Fn14 >90% inconsis. inhibits transmenmbrane protein SW620, SW620, 231 231  12 9 cadherin 3, P-cadherin CDH3 CADHERIN-P >90% Inhib in Inhib in (placental) SW620 SW620  16 13 kallikrein 6 (neurosin, KLK6 proteaseM >80% weak effect negative zyme) in SW620 SW620  38 33 transketolase (Wemicke- TKT TRANSKETOLASE >90% inconsis. inhibits Korsakoff syndrome) SW620, SW620, 231 231  42 37 6-pyruvoyl- PCBD hDohc >95% inconsis. inhibits tetrahydropterin SW620, SW620, synthase/dimerization 231 231 cofactor of hepatocyte nuclear factor 1 alpha (TCF1)  56 53 hECT2 >80% Inhib in Inhib in SW620 SW620  63 63 dipeptidase 1 (renal) DPEP1 DPP >80% weak negative inhibition in SW620  77 75 tetraspan 5 TSPAN-5 NET-4 >90% Inhib in weak SW620 inhibition 180 193 S-adenosylhomocysteine AHCY HUMAHCY 2 >70% Inhib in Inhib in hydrolase SW620 SW620 233 263 polo (Drosophia)-like PLK PLK1 >90% Inhib in Inhib in kinase SW620 SW620 236 266 serum-inducible kinase SNK SNK >80% Inhib in negative SW620 in SW620 253 280 v-akt murine thymoma AKT3 AKT3 >90% inhibits inhibits viral oncogene homolog 3 SKOV3, 231 SKOV3, (protein kinase B, gamma) 231 279 239 AI335279 >90% negative in weak SW620 inhibition 300 249 TTK protein kinase TTK hTTK >90% inhibits inhibits SW620 SW620 247, 236 serine/threonine kinase 15 STK15 hARK2 >80% Inhib in weak 290 SW620 effect in SW620 257, 212 cyclin-dependent kinase CDKN3 KAP >85% Inhib in 268 inhibitor 3 (CDK2- SW620 associated dual specificity phosphatase) 35, 30 CDC28 protein kinase 1 CKS1 CKS1 >80% Inhib in Inhib in 150 SW620 SW620 88, 118 c3376 >80% weak effect neg 196 in SW620 SW620

Example 5 Effect of Gene Expression on Colony Formation

The effect of gene expression upon colony formation of SW620 cells, SKOV3 cells, and MD-MBA-231 cells was tested in a soft agar assay. Soft agar assays were conducted by first establishing a bottom layer of 2 ml of 0.6% agar in media plated fresh within a few hours of layering on the cells. The cell layer was formed on the bottom layer by removing cells transfected as described above from plates using 0.05% trypsin and washing twice in media. The cells were counted in a Coulter counter, and resuspended to 10⁶ per ml in media. 10 μl aliquots were placed with media in 96-well plates (to check counting with WST1), or diluted further for the soft agar assay. 2000 cells were plated in 800 μl 0.4% agar in duplicate wells above 0.6% agar bottom layer. After the cell layer agar solidified, 2 ml of media was dribbled on top and antisense or reverse control oligo (produced as described in Example 3) was added without delivery vehicles. Fresh media and oligos were added every 3-4 days. Colonies formed in 10 days to 3 weeks. Fields of colonies were counted by eye. Wst-1 metabolism values can be used to compensate for small differences in starting cell number. Larger fields can be scanned for visual record of differences.

Table 8 (inserted before the claims) provides the results of these assays (“Softagar”). Those antisense oligonucleotides that resulted in inhibition of colony formation are indicated by “inhibits”, “weak effect”, or “weak inhibition” followed by the cell type. Those antisense oligonucleotides that resulted in inhibition of colony formation of SW620 cells indicates that the corresponding gene plays a role in production or maintenance of the cancerous phenotype in cancerous colon cells. Those antisense oligonucleotides that inhibited colony formation in SKOV3 cells represent genes that play a role in production or maintenance of the cancerous phenotype in cancerous breast cells. Those antisense oligonucleotides that resulted in inhibition of colony formation of MDA-MB-231 cells indicates that the corresponding gene plays a role in production or maintenance of the cancerous phenotype in cancerous ovarian cells.

Example 6 Induction of Cell Death Upon Depletion of Polypeptides by Depletion of mRNA (“Antisense Knockout”)

In order to assess the effect of depletion of a target message upon cell death, SW620 cells, or other cells derived from a cancer of interest, are transfected for proliferation assays. For cytotoxic effect in the presence of cisplatin (cis), the same protocol is followed but cells are left in the presence of 2 μM drug. Each day, cytotoxicity was monitored by measuring the amount of LDH enzyme released in the medium due to membrane damage. The activity of LDH is measured using the Cytotoxicity Detection Kit from Roche Molecular Biochemicals. The data is provided as a ratio of LDH released in the medium vs. the total LDH present in the well at the same time point and treatment (rLDH/tLDH). A positive control using antisense and reverse control oligonucleotides for BCL2 (a known anti-apoptotic gene) is included; loss of message for BCL2 leads to an increase in cell death compared with treatment with the control oligonucleotide (background cytotoxicity due to transfection).

Example 7 Functional Analysis of Gene Products Differentially Expressed in Colon Cancer in Patients

The gene products of sequences of a gene differentially expressed in cancerous cells can be further analyzed to confirm the role and function of the gene product in tumorigenesis, e.g., in promoting or inhibiting development of a metastatic phenotype. For example, the function of gene products corresponding to genes identified herein can be assessed by blocking function of the gene products in the cell. For example, where the gene product is secreted or associated with a cell surface membrane, blocking antibodies can be generated and added to cells to examine the effect upon the cell phenotype in the context of, for example, the transformation of the cell to a cancerous, particularly a metastatic, phenotype.

Where the gene product of the differentially expressed genes identified herein exhibits sequence homology to a protein of known function (e.g., to a specific kinase or protease) and/or to a protein family of known function (e.g., contains a domain or other consensus sequence present in a protease family or in a kinase family), then the role of the gene product in tumorigenesis, as well as the activity of the gene product, can be examined using small molecules that inhibit or enhance function of the corresponding protein or protein family.

Additional functional assays include, but are not necessarily limited to, those that analyze the effect of expression of the corresponding gene upon cell cycle and cell migration. Methods for performing such assays are well known in the art.

Example 8 Contig Assembly and Additional Gene Characterization

The sequences of the polynucleotides provided in the present invention can be used to extend the sequence information of the gene to which the polynucleotides correspond (e.g., a gene, or mRNA encoded by the gene, having a sequence of the polynucleotide described herein). This expanded sequence information can in turn be used to further characterize the corresponding gene, which in turn provides additional information about the nature of the gene product (e.g., the normal function of the gene product). The additional information can serve to provide additional evidence of the gene product's use as a therapeutic target, and provide further guidance as to the types of agents that can modulate its activity.

In one example, a contig was assembled using the sequence of the polynucleotide having SEQ ID NO:2 (sequence name 019.G3.sp6_(—)128473), which is present in clone M00006883D:H12. A “contig” is a contiguous sequence of nucleotides that is assembled from nucleic acid sequences having overlapping (e.g., shared or substantially similar) sequence information. The sequences of publicly-available ESTs (Expressed Sequence Tags) and the sequences of various clones from several cDNA libraries synthesized at Chiron were used in the contig assembly. None of the sequences from these latter clones from the cDNA libraries had significant hits against known genes with function when searched using BLASTN against GenBank as described above.

The contig was assembled using the software program Sequencher, version 4.05, according to the manufacturer's instructions. The final contig was assembled from 11 sequences, provided in the Sequence Listing as SEQ ID NOS:2 and 310-320. The sequence names and SEQ ID NOS of the sequences are provided in the overview alignment produced by Sequencher (see FIG. 1).

The clone containing the sequence of 035JN032.H09 (SEQ ID NO:319) is of particular interest. This clone was originally obtained from a normalized cDNA library prepared from a prostate cancer tissue sample that was obtained from a patient with Gleason grade 3+3. The clone having the 035JN032.H09 sequence corresponds to a gene that has increased expression in (e.g., is upregulated) in colon cancer as detected by microarray analysis using the protocol and materials described above. The data is provided in the table below. Number of SEQ patients used ID Spot Chip Sample to calculate % % NO ID # ID concordance >=2x >=5x 2 1833 1 M00006883D:H12 33 61 33 319 27454 5 035JN032.H09 28 61 11

“%>2×” and “%>5×” indicate the percentage of patients in which the corresponding gene was expressed at two-fold and five-fold greater levels in cancerous cells relative to normal cells, respectively.

This observation thus further validates the expression profile of the clone having the sequence of 035JN032.H09, as it indicates that the gene represented by this sequence and clone is differentially expressed in at least two different cancer types.

The sequence information obtained in the contig assembly described above was used to obtain a consensus sequence derived from the contig using the Sequencher program. The consensus sequence is provided as SEQ ID NO:320 in the Sequence Listing.

In preliminary experiments, the consensus sequence was used as a query sequence in a BLASTN search of the DGTI DoubleTwist Gene Index (DoubleTwist, Inc., Oakland, Calif.), which contains all the EST and non-redundant sequence in public databases. This preliminary search indicated that the consensus sequence has homology to a predicted gene homologue to human atrophin-1 (HSS0190516.1 dtgic|HSC010416.3 Similar to: DRPL_HUMAN gi|17660|sp|P54259|DRPL_HUMAN ATROPHIN-1 (DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY PROTEIN) [Homo sapiens (Human), provided as SEQ ID NO:322), with a Score=1538 bits (776), Expect=0.0, and Identities=779/780 (99%).

While the preliminary results regarding the homology to atrophin-1 are not yet confirmed, this example, through contig assembly and the use of homology searching software programs, shows that the sequence information provided herein can be readily extended to confirm, or confirm a predicted, gene having the sequence of the polynucleotides described in the present invention. Further the information obtained can be used to identify the function of the gene product of the gene corresponding to the polynucleotides described herein. While not necessary to the practice of the invention, identification of the function of the corresponding gene, can provide guidance in the design of therapeutics that target the gene to modulate its activity and modulate the cancerous phenotype (e.g., inhibit metastasis, proliferation, and the like).

Example 9 Source of Biological Materials

The biological materials used in the experiments that led to the present invention are described below.

Source of Patient Tissue Samples

Normal and cancerous tissues were collected from patients using laser capture microdissection (LCM) techniques, which techniques are well known in the art (see, e.g., Ohyama et al. (2000) Biotechniques 29:530-6; Curran et al. (2000) Mol. Pathol. 53:64-8; Suarez-Quian et al. (1999) Biotechniques 26:328-35; Simone et al. (1998) Trends Genet 14:272-6; Conia et al. (1997) J. Clin. Lab. Anal. 11:28-38; Emmert-Buck et al. (1996) Science 274:998-1001). Table 10 (inserted prior to claims) provides information about each patient from which colon tissue samples were isolated, including: the Patient ID (“PT ID”) and Path ReportID (“Path ID”), which are numbers assigned to the patient and the pathology reports for identification purposes; the group (“Grp”) to which the patients have been assigned; the anatomical location of the tumor (“Anatom Loc”); the primary tumor size (“Size”); the primary tumor grade (“Grade”); the identification of the histopathological grade (“Histo Grade”); a description of local sites to which the tumor had invaded (“Local Invasion”); the presence of lymph node metastases (“Lymph Met”); the incidence of lymph node metastases (provided as a number of lymph nodes positive for metastasis over the number of lymph nodes examined) (“Lymph Met Incid”); the regional lymphnode grade (“Reg Lymph Grade”); the identification or detection of metastases to sites distant to the tumor and their location (“Dist Met & Loc”); the grade of distant metastasis (“Dist Met Grade”); and general comments about the patient or the tumor (“Comments”). Histophatology of all primary tumors indicated the tumor was adenocarcinoma except for Patient ID Nos. 130 (for which no information was provided), 392 (in which greater than 50% of the cells were mucinous carcinoma), and 784 (adenosquamous carcinoma). Extranodal extensions were described in three patients, Patient ID Nos. 784 and 791. Lymphovascular invasion was described in Patient ID Nos. 128, 228, 278, 517, 784, 786, 791, and 890. Crohn's-like infiltrates were described in seven patients, Patient ID Nos. 52, 264, 268, 392, 393, 784, and 791. TABLE 10 Lymph Reg Dist Dist Pt Path Anatom Histo Lymph Met Lymph Met & Met ID ID Grp Loc Size Grade Grade Local Invasion Met Incid Grade Loc Grade Comment 15 21 III Ascending 4.0 T3 G2 Extending into Pos 3/8  N1 Neg MX invasive colon subserosal adipose adenocarcinoma, tissue moderately differentiated; focal perineural invasion is seen 52 71 II Cecum 9.0 T3 G3 Invasion through Neg 0/12 N0 Neg M0 Hyperplastic muscularis propria, polyp in subserosal appendix. involvement; ileocec. valve involvement 121 140 II Sigmoid 6 T4 G2 Invasion of Neg 0/34 N0 Neg M0 Perineural muscularis propria invasion; into serosa, donut involving anastomosis submucosa of Neg. One urinary bladder tubulovillous and one tubular adenoma with no high grade dysplasia. 125 144 II Cecum 6 T3 G2 Invasion through Neg 0/19 N0 Neg M0 patient the muscularis history of propria into metastatic suserosal adipose melanoma tissue. Ileocecal junction. 128 147 III Transverse 5.0 T3 G2 Invasion of Pos 1/5  N1 Neg M0 colon muscularis propria into percolonic fat 130 149 Splenic 5.5 T3 through wall and Pos 10/24  N2 Neg M1 flexure into surrounding adipose tissue 133 152 II Rectum 5.0 T3 G2 Invasion through Neg 0/9  N0 Neg M0 Small muscularis propria separate into non- tubular peritonealized adenoma (0.4 cm) pericolic tissue; gross configuration is annular. 141 160 IV Cecum 5.5 T3 G2 Invasion of Pos 7/21 N2 Pos - M1 Perineural muscularis propria Liver invasion into pericolonic identified adipose tissue, but adjacent to not through serosa. metastatic Arising from adenocarcinoma. tubular adenoma. 156 175 III Hepatic 3.8 T3 G2 Invasion through Pos 2/13 N1 Neg M0 Separate flexure mucsularis propria tubolovillous into and tubular subserosa/pericolic adenomas adipose, no serosal involvement. Gross configuration annular. 228 247 III Rectum 5.8 T3 G2 to Invasion through Pos 1/8  N1 Neg MX Hyperplastic G3 muscularis propria polyps to involve subserosal, perirectoal adipose, and serosa 264 283 II Ascending 5.5 T3 G2 Invasion through Neg 0/10 N0 Neg M0 Tubulovillous colon muscularis propria adenoma with into subserosal high grade adipose tissue. dysplasia 266 285 III Transverse 9 T3 G2 Invades through Neg 0/15 N1 Pos - MX colon muscularis propria Mesen- to involve teric pericolonic deposit adipose, extends to serosa. 268 287 I Cecum 6.5 T2 G2 Invades full Neg 0/12 N0 Neg M0 thickness of muscularis propria, but mesenteric adipose free of malignancy 278 297 III Rectum 4 T3 G2 Invasion into Pos 7/10 N2 Neg M0 Descending perirectal adipose colon polyps, tissue. no HGD or carcinoma identified. 295 314 II Ascending 5.0 T3 G2 Invasion through Neg 0/12 N0 Neg M0 Melanosis colon muscularis propria coli and into percolic diverticular adipose tissue. disease. 296 315 III Cecum 5.5 T3 G2 Invasion through Pos 2/12 N1 Neg M0 Tubulovillous muscularis propria adenoma (2.0 cm) and invades with no pericolic adipose high grade tissue. Ileocecal dysplasia. junction. Neg. liver biopsy. 339 358 II Recto- 6 T3 G2 Extends into Neg 0/6  N0 Neg M0 1 hyperplastic sigmoid perirectal fat but polyp does not reach identified serosa 341 360 II Ascending 2 cm T3 G2 Invasion through Neg 0/4  N0 Neg MX colon invasive muscularis propria to involve pericolonic fat. Arising from villous adenoma. 356 375 II Sigmoid 6.5 T3 G2 Through colon wall Neg 0/4  N0 Neg M0 into subserosal adipose tissue. No serosal spread seen. 392 444 IV Ascending 2 T3 G2 Invasion through Pos 1/6  N1 Pos - M1 Tumor colon muscularis propria Liver arising at into subserosal prior ileocolic adipose tissue, not surgical serosa. anastomosis. 393 445 II Cecum 6.0 T3 G2 Cecum, invades Neg 0/21 N0 Neg M0 through muscularis propria to involve subserosal adipose tissue but not serosa. 413 465 IV Cecum 4.8 T3 G2 Invasive through Neg 0/7  N0 Pos - M1 rediagnosis of muscularis to Liver oophorectomy involve periserosal path to fat; abutting metastatic ileocecal junction. colon cancer. 517 395 IV Sigmoid 3 T3 G2 penetrates Pos 6/6  N2 Neg M0 No mention muscularis propria, of distant met involves in report pericolonic fat. 546 565 IV Ascending 5.5 T3 G2 Invasion through Pos 6/12 N2 Pos M1 colon Liver muscularis propria extensively through submucosal and extending to serosa. 577 596 II Cecum 11.5 T3 G2 Invasion through Neg 0/58 N0 Neg M0 Appendix the bowel wall, into dilated and suberosal adipose. fibrotic, but Serosal surface free not involved of tumor. by tumor 784 803 IV Ascending 3.5 T3 G3 through muscularis Pos 5/17 N2 Pos - M1 invasive colon propria into Liver poorly pericolic soft differentiated tissues adenosquamous carcinoma 786 805 IV Descend- 9.5 T3 G2 through muscularis Neg 0/12 N0 Pos - M1 moderately ing colon propria into Liver differentiated pericolic fat, but invasive not at serosal adenocarcinoma surface 791 810 IV Ascending 5.8 T3 G3 Through the Pos 13/25 N2 Pos - M1 poorly colon muscularis propria Liver differentiated into pericolic fat invasive colonic adenocarcinoma 888 908 IV Ascending 2.0 T2 G1 Into muscularis Pos 3/21 N0 Pos - M1 well to colon propria Liver moderately differentiated adenocarcinomas; this patient has tumors of the ascending colon and the sigmoid colon 889 909 IV Cecum 4.8 T3 G2 Through Pos 1/4  N1 Pos - M1 moderately muscularis propria Liver differentiated int subserosal adenocarcinoma tissue 890 910 IV Ascending T3 G2 Through Pos 11/15  N2 Pos - M1 colon Liver muscularis propria into subserosa.

Source of Polynucleotides on Arrays

Polynucleotides for use on the arrays were obtained from both publicly available sources and from cDNA libraries generated from selected cell lines and patient tissues. Table 11 (inserted prior to claims) provides information about the polynucleotides on the arrays including: (1) the “SEQ ID NO” assigned to each sequence for use in the present specification; (2) the spot identification number (“Spot ID”), an internal reference that serves as a unique identifier for the spot on the array; (3) the “Clone ID” assigned to the clone from which the sequence was isolated; (4) the number of the Group (“Grp”) to which the gene is assigned (see Example 11 below); and (5) the gene represented by the SEQ ID NO (“Gene”). TABLE 11 SEQ ID Spot NO ID Clone ID Grp Gene GBHit GBDesc GBScore 322 33669 RG:26148:Order7TM01:C06 1 IGF2 X07868 Human DNA for insulin- 2.1E−35 like growth factor II (IGF-2); exon 7 and additional ORF 323 32956 RG:240381:Order7TM20:G11 1 IGF2 X03427 Homo sapiens IGF-II 7.4E−186 gene, exon 5 324 17167 RG:730402:10010:H01 1 TTK BC000633 Homo sapiens, TTK 2.1E−38  protein kinase, clone MGC: 865 IMAGE: 3343925, mRNA, complete cds 325 21711 RG:1674098:10014:H01 1 MARCKS D10522 Homo sapiens mRNA for   4E−148 80K-L protein, complete cds 326 29171 035JN025.C12 1 FLJ22066 AK025719 Homo sapiens cDNA: 0 FLJ22066 fis, clone HEP10611 327 30566 RG:432087:Order7TM26:D02 1 FLJ22066 AK025719 Homo sapiens cDNA: 0 FLJ22066 fis, clone HEP10611 328 10638 I:1644648:07B01:G04 1 NQO2 U07736 Human quinone 1.6E−171 oxidoreductase2 (NQO2) gene, exon 7, complete cds 329 8491 I:2594080:05A01:F01 1 FHL3 BC001351 Homo sapiens, Similar to 2.6E−34 four and a half LIM domains 3, clone MGC: 8696 IMAGE: 2964682, mRNA, compl 330 27092 035Jn031.C09 1 MGC: 29604 BC019103 Homo sapiens, clone   1E−300 MGC: 29604 IMAGE: 5021401, mRNA, complete cds 331 10394 I:1450639:03B02:E09 1 CETN2 BC005334 Homo sapiens, centrin, 1.1E−190 EF-hand protein, 2, clone MGC: 12421 IMAGE: 3961448, mRNA, complete cds 332 3295 M00008083D:D06 1 CGI-148 AF223467 Homo sapiens NPD008 2.5E−157 protein protein (NPD008) mRNA, complete cds 333 30831 RG:301734:Order7TM22:H02 1 KIP2 AB012955 Homo sapiens mRNA for 5.8E−252 KIP2, complete cds 334 19871 RG:196236:10006:H11 1 FGFR4 AF359246 Homo sapiens fibroblast   5E−249 growth factor receptor 4 variant mRNA, complete cds 335 30858 RG:359021:Order7TM24:F02 1 BBS2 AF342736 Homo sapiens BBS2   1E−100 (BBS2) mRNA, complete cds 336 17168 RG:1320327:10012:H01 1 OGG1 Y11731 H. sapiens mRNA for   1E−300 DNA glycosylase 337 17487 RG:341475:10008:H01 1 MAPKAPK2 NM_032960 Homo sapiens mitogen- 1E−300 activated protein kinase- activated protein kinase 2 (MAPKAPK2), transcript variant 338 18942 RG:1895716:10015:G09 2 ITAK AC007055 AC007055 Homo sapiens 3.00E−94  chromosome 14 clone BAC 201F1 map 14q24.3, complete sequence 339 17365 I:504786:14A02:C07 2 1-8U; 1-8D; BC006794 Homo sapiens, Similar to 6.4E−295 9-27 interferon induced transmembrane protein 3 (1-8U), clone MGC: 5225 IMAGE: 340 21144 M00055353D:A04 2 1-8U; 1-8D; BC006794 Homo sapiens, Similar to 1.1E−156 9-27 interferon induced transmembrane protein 3 (1-8U), clone MGC: 5225 IMAGE: 341 11573 I:1513214:04A01:C11 2 BIRC3 U45878 Human inhibitor of 2.5E−157 apoptosis protein 1 mRNA, complete cds

The sequences corresponding to the SEQ ID NOS are provided in the Sequence Listing.

Characterization of Sequences

The sequences of the isolated polynucleotides were first masked to eliminate low complexity sequences using the RepeatMasker masking program, publicly available through a web site supported by the University of Washington (See also Smit, A. F. A. and Green, P., unpublished results). Generally, masking does not influence the final search results, except to eliminate sequences of relatively little interest due to their low complexity, and to eliminate multiple “hits” based on similarity to repetitive regions common to multiple sequences, e.g., Alu repeats. Masking resulted in the elimination of several sequences.

The remaining sequences of the isolated polynucleotides were used in a homology search of the GenBank database using the TeraBLAST program (TimeLogic, Crystal Bay, Nev.), a DNA and protein sequence homology searching algorithm. TeraBLAST is a version of the publicly available BLAST search algorithm developed by the National Center for Biotechnology, modified to operate at an accelerated speed with increased sensitivity on a specialized computer hardware platform. The program was run with the default parameters recommended by TimeLogic to provide the best sensitivity and speed for searching DNA and protein sequences. Gene assignment for the query sequences was determined based on best hit form the GenBank database; expectancy values are provided with the hit.

Summary of TeraBLAST Search Results

Table 11 also provides information about the gene corresponding to each polynucleotide. Table 11 includes: (1) the “SEQ ID NO” of the sequence; (2) the GenBank Accession Number of the publicly available sequence corresponding to the polynucleotide (“GBHit”); (3) a description of the GenBank sequence (“GBDesc”); (4) the score of the similarity of the polynucleotide sequence and the GenBank sequence (“GBScore”). The published information for each GenBank and EST description, as well as the corresponding sequence identified by the provided accession number, are incorporated herein by reference.

Example 10 Detection of Differential Expression Using Arrays

cDNA probes were prepared from total RNA isolated from the patient cells described above. Since LCM provides for the isolation of specific cell types to provide a substantially homogenous cell sample, this provided for a similarly pure RNA sample.

Total RNA was first reverse transcribed into cDNA using a primer containing a T7 RNA polymerase promoter, followed by second strand DNA synthesis. cDNA was then transcribed in vitro to produce antisense RNA using the T7 promoter-mediated expression (see, e.g., Luo et al. (1999) Nature Med 5:117-122), and the antisense RNA was then converted into cDNA. The second set of cDNAs were again transcribed in vitro, using the T7 promoter, to provide antisense RNA. Optionally, the RNA was again converted into cDNA, allowing for up to a third round of T7-mediated amplification to produce more antisense RNA. Thus the procedure provided for two or three rounds of in vitro transcription to produce the final RNA used for fluorescent labeling.

Fluorescent probes were generated by first adding control RNA to the antisense RNA mix, and producing fluorescently labeled cDNA from the RNA starting material. Fluorescently labeled cDNAs prepared from the tumor RNA sample were compared to fluorescently labeled cDNAs prepared from normal cell RNA sample. For example, the cDNA probes from the normal cells were labeled with Cy3 fluorescent dye (green) and the cDNA probes prepared from the tumor cells were labeled with Cy5 fluorescent dye (red), and vice versa.

Each array used had an identical spatial layout and control spot set. Each microarray was divided into two areas, each area having an array with, on each half, twelve groupings of 32×12 spots, for a total of about 9,216 spots on each array. The two areas are spotted identically which provide for at least two duplicates of each clone per array.

Polynucleotides for use on the arrays were obtained from both publicly available sources and from cDNA libraries generated from selected cell lines and patient tissues as described above and in Table 11. PCR products of from about 0.5 kb to 2.0 kb amplified from these sources were spotted onto the array using a Molecular Dynamics Gen III spotter according to the manufacturer's recommendations. The first row of each of the 24 regions on the array had about 32 control spots, including 4 negative control spots and 8 test polynucleotides. The test polynucleotides were spiked into each sample before the labeling reaction with a range of concentrations from 2-600 pg/slide and ratios of 1:1. For each array design, two slides were hybridized with the test samples reverse-labeled in the labeling reaction. This provided for about four duplicate measurements for each clone, two of one color and two of the other, for each sample.

The differential expression assay was performed by mixing equal amounts of probes from tumor cells and normal cells of the same patient. The arrays were prehybridized by incubation for about 2 hrs at 60° C. in 5×SSC/0.2% SDS/1 mM EDTA, and then washed three times in water and twice in isopropanol. Following prehybridization of the array, the probe mixture was then hybridized to the array under conditions of high stringency (overnight at 42° C. in 50% formamide, 5×SSC, and 0.2% SDS. After hybridization, the array was washed at 55° C three times as follows: 1) first wash in 1×SSC/0.2% SDS; 2) second wash in 0.1×SSC/0.2% SDS; and 3) third wash in 0.1×SSC.

The arrays were then scanned for green and red fluorescence using a Molecular Dynamics Generation III dual color laser-scanner/detector. The images were processed using BioDiscovery Autogene software, and the data from each scan set normalized to provide for a ratio of expression relative to normal. Data from the microarray experiments was analyzed according to the algorithms described in U.S. application serial no. 60/252,358, filed Nov. 20, 2000, by E. J. Moler, M. A. Boyle, and F. M. Randazzo, and entitled “Precision and accuracy in cDNA microarray data,”which application is specifically incorporated herein by reference.

The experiment was repeated, this time labeling the two probes with the opposite color in order to perform the assay in both “color directions.” Each experiment was sometimes repeated with two more slides (one in each color direction). The level fluorescence for each sequence on the array expressed as a ratio of the geometric mean of 8 replicate spots/genes from the four arrays or 4 replicate spots/gene from 2 arrays or some other permutation. The data were normalized using the spiked positive controls present in each duplicated area, and the precision of this normalization was included in the final determination of the significance of each differential. The fluorescent intensity of each spot was also compared to the negative controls in each duplicated area to determine which spots have detected significant expression levels in each sample.

A statistical analysis of the fluorescent intensities was applied to each set of duplicate spots to assess the precision and significance of each differential measurement, resulting in a p-value testing the null hypothesis that there is no differential in the expression level between the tumor and normal samples of each patient. During initial analysis of the microarrays, the hypothesis was accepted if p>10⁻³, and the differential ratio was set to 1.000 for those spots. All other spots have a significant difference in expression between the tumor and normal sample. If the tumor sample has detectable expression and the normal does not, the ratio is truncated at 1000 since the value for expression in the normal sample would be zero, and the ratio would not be a mathematically useful value (e.g., infinity). If the normal sample has detectable expression and the tumor does not, the ratio is truncated to 0.001, since the value for expression in the tumor sample would be zero and the ratio would not be a mathematically useful value. These latter two situations are referred to herein as “on/off.” Database tables were populated using a 95% confidence level (p>0.05).

Tables 12A-D summarizes the results of the differential expression analysis. Table 12 provides: (1) the spot identification number (“Spot ID”), an internal reference that serves as a unique identifier for the spot on the array; (2) the number of the Group (“Grp”) to which the gene is assigned (see Example 11 below); and (3) the ratio of expression of the gene in each of the patient samples, identified by the patient ID number (e.g., 15). This data represents the ratio of differential expression for the samples tested from that particular patient's tissues (e.g., “1RATIO15” is the ratio from the tissue samples of Patient ID no. 15). The ratios of differential expression are expressed as a normalized hybridization signal associated with the tumor probe divided by the normalized hybridization signal with the normal probe. Thus, a ratio greater than 1 indicates that the gene product is increased in expression in cancerous cells relative to normal cells, while a ratio of less than 1 indicates the opposite. TABLE 12A RATIO RATIO RATIO RATIO RATIO RATIO RATIO RATIO RATIO Spot ID Grp Gene 015 052 121 125 128 130 133 141 156 3295 1 CGI-148 protein 0.603 0.569 1.420 1.000 1.347 0.544 1.000 0.663 0.400 8491 1 FHL3 1.000 1.000 10.786 6.347 4.580 2.918 5.331 1.000 2.771 10394 1 CETN2 1.000 1.000 3.335 1.000 2.493 2.450 1.000 1.000 2.130 10638 1 NQO2 1.000 1.000 2.522 1.720 2.495 1.000 1.748 1.000 2.018 17167 1 TTK 1.000 1.000 5.053 1.000 5.484 1.000 1.000 1.000 1.000 17168 1 OGG1 1.389 1.000 1.736 1.000 2.525 1.000 2.339 1.000 1.162 17487 1 MAPKAPK2 1.000 1.000 39.041 1.000 26.551 1.000 54.030 0.657 0.116 19871 1 FGFR4 1.000 1.000 4.040 0.760 3.246 1.000 4.017 1.859 0.224 21711 1 MARCKS 1.000 1.000 21.440 1.294 10.369 1.000 20.040 1.000 1.000 27092 1 MGC:29604 1.806 2.418 5.831 2.114 11.273 1.821 9.841 1.413 2.385 29171 1 FLJ22066 1.000 1.000 184.016 0.728 52.758 0.849 145.030 1.000 0.015 30566 1 FLJ22066 1.000 1.000 163.068 1.000 53.616 1.000 1.000 1.000 0.083 30831 1 KIP2 0.723 1.000 2.349 1.000 1.972 1.000 1.000 1.437 0.626 30858 1 BBS2 1.304 0.745 1.907 1.678 2.686 0.525 1.877 1.000 0.251 32956 1 IGF2 1.105 1.000 20.747 1.000 10.458 1.000 1.000 1.000 0.476 33669 1 IGF2 0.592 0.381 21.028 1.195 16.876 0.334 25.468 0.720 0.049 11573 2 BIRC3 1.698 2.791 0.825 1.319 1.264 1.587 1.986 0.408 1.504 17365 2 1-8U; 1-8D; 9-27 3.113 2.893 1.229 4.848 3.307 4.004 9.166 1.000 1.769 18942 2 ITAK 4.489 7.386 1.000 6.655 4.507 5.485 12.390 1.000 2.281 21144 2 1-8U; 1-8D; 9-27 5.520 22.946 1.000 5.929 3.918 7.337 8.908 1.182 1.706

TABLE 12B RATIO RATIO RATIO RATIO RATIO RATIO RATIO RATIO RATIO Spot ID Grp Gene 228 264 266 268 278 295 296 339 341 3295 1 CGI-148 protein 0.579 0.599 0.302 1.000 1.270 1.000 0.484 0.561 1.000 8491 1 FHL3 1.000 1.000 1.000 12.583 4.691 1000.000 1000.000 3.136 7.320 10394 1 CETN2 1.000 1.000 1.000 3.463 1.000 1.000 1000.000 1.000 4.065 10638 1 9 1.000 1.000 1.000 3.325 1.697 1.000 1000.000 1.000 3.036 17167 1 TTK 1.000 1.724 1.515 1.000 1.000 1.000 1000.000 1.000 5.355 17168 1 OGG1 1.000 1.584 1.332 2.564 2.024 1.600 1.551 0.739 1.999 17487 1 MAPKAPK2 1.000 1.000 1.206 43.580 23.642 2.085 1.000 0.545 18.309 19871 1 FGFR4 1.619 1.992 1.000 4.407 3.989 1000.000 1.000 1.324 2.494 21711 1 MARCKS 1.000 1.000 1.192 13.283 1.000 2.161 1.000 0.638 1.000 27092 1 MGC:29604 1.927 3.330 2.678 10.984 9.190 4.226 8.035 0.757 14.757 29171 1 FLJ22066 1.000 1.760 1.000 186.617 83.660 4.242 1000.000 0.303 102.601 30566 1 FLJ22066 1.596 1.430 1.000 108.781 51.686 1.000 1.000 0.530 50.061 30831 1 KIP2 0.672 0.952 1.000 1.000 2.848 1.000 1.000 1.000 2.521 30858 1 BBS2 1.393 1.547 1.431 2.272 1.440 1.000 1.000 1.000 2.180 32956 1 IGF2 1.000 1.000 1.000 32.991 3.788 1.000 1.000 1.565 10.202 33669 1 IGF2 0.566 0.380 0.196 14.331 4.654 0.298 0.237 0.508 11.442 11573 2 BIRC3 1.000 1.645 1.000 1.283 1.667 1.408 2.084 1.000 1.000 17365 2 1-8U; 1-8D; 9-27 2.633 7.263 7.775 4.152 4.770 3.064 2.220 1.374 1.808 18942 2 ITAK 4.106 10.286 11.733 6.840 1.000 11.385 1.000 1.892 1.690 21144 2 1-8U; 1-8D; 9-27 5.027 8.086 8.148 3.902 7.228 5.159 1.000 2.787 1.569

TABLE 12C RATIO RATIO RATIO RATIO RATIO RATIO RATIO RATIO RATIO Spot ID Grp Gene 356 392 393 413 517 546 577 784 786 3295 1 CGI-148 protein 0.503 0.816 0.692 0.649 0.200 1.000 1.000 0.662 0.532 8491 1 FHL3 1.000 1.000 13.185 1.000 1000.000 3.131 5.278 1.000 1.000 10394 1 CETN2 1000.000 1.000 3.015 1.000 1.000 1.000 1.000 1.000 1.000 10638 1 NQO2 1.000 1.000 2.850 1.000 1.000 1.000 1.000 1.000 1.000 17167 1 TTK 1.000 1.000 5.355 1.000 1.000 1.000 3.158 1.092 1.898 17168 1 OGG1 1.000 2.116 1.694 1.000 1.000 1.000 1.672 1.701 1.000 17487 1 MAPKAPK2 1.556 51.316 43.253 0.516 1.412 0.813 1.000 1.000 1.000 19871 1 FGFR4 1.000 2.284 4.041 1.000 3.005 2.185 1.000 1.000 3.307 21711 1 MARCKS 1.000 32.171 26.574 0.814 1.000 1.000 1.347 1.000 1.000 27092 1 MGC:29604 7.284 12.948 8.685 1.742 1.451 2.296 3.357 1.329 2.919 29171 1 FLJ22066 1.000 218.198 197.610 0.330 1.657 0.749 1.000 1.000 1.790 30566 1 FLJ22066 1.000 264.417 157.238 0.293 1.300 1.000 1.220 2.785 1.000 30831 1 KIP2 1.000 1.997 1.964 1.000 1.379 1.119 0.753 1.972 1.000 30858 1 BBS2 0.519 3.152 2.475 3.013 0.449 1.000 0.662 1.339 1.000 32956 1 IGF2 1.475 25.053 23.953 1.000 1.529 1.430 1.600 1.430 1.713 33669 1 IGF2 0.412 24.283 30.632 0.564 0.214 0.853 0.381 0.551 0.506 11573 2 BIRC3 1.000 1.199 1.768 1.000 1.485 1.000 1.429 1.000 1.648 17365 2 1-8U; 1-8D; 9-27 3.636 9.985 7.293 2.980 4.484 3.107 4.362 1.645 4.670 18942 2 ITAK 12.611 16.163 7.279 3.603 6.904 4.196 7.792 1.000 8.475 21144 2 1-8U; 1-8D; 9-27 10.080 18.239 8.395 2.839 6.176 3.328 5.636 2.142 7.000

TABLE 12D RATIO RATIO RATIO RATIO Spot ID Grp Gene 791 888 889 890 3295 1 CGI-148 protein 0.495 0.574 0.483 0.711 8491 1 FHL3 1.000 1.000 1.000 5.465 10394 1 CETN2 1.000 2.970 1.000 2.848 10638 1 NQO2 1.000 1.511 1.000 2.158 17167 1 TTK 1.000 1.000 1.000 2.290 17168 1 OGG1 1.000 1.000 1.000 1.519 17487 1 MAPKAPK2 1.000 1.449 1.000 1.516 19871 1 FGFR4 1.000 1.988 0.646 4.007 21711 1 MARCKS 1.000 1.397 1.000 1.000 27092 1 MGC:29604 3.771 1.890 2.788 1.799 29171 1 FLJ22066 1.000 1.000 7.569 2.512 30566 1 FLJ22066 1.000 2.624 1.000 1.713 30831 1 KIP2 1.000 1.000 1.000 4.213 30858 1 BBS2 0.749 2.316 0.506 1.000 32956 1 IGF2 1.486 1.633 1.000 1.491 33669 1 IGF2 0.474 0.842 2.502 0.736 11573 2 BIRC3 2.502 0.781 1.314 1.000 17365 2 1-8U; 1-8D; 9-27 8.576 2.723 3.553 11.697 18942 2 ITAK 10.189 2.909 4.165 11.972 21144 2 1-8U; 1-8D; 9-27 14.444 2.712 7.659 11.467

These data provide evidence that the genes represented by the polynucleotides having the indicated sequences are differentially expressed in colon cancer as compared to normal non-cancerous colon tissue.

Example 11 Stratification of Colon Cancers Using Differential Expression Data

Groups of genes with differential expression data correlating with specific genes of interest can be identified using statistical analysis such as the Student t-test and Spearman rank correlation (Stanton Glantz (1997) Primer of Bio-Statistics, McGraw Hill, pp 65-107, 256-262). Using these statistical tests, patients having tumors that exhibit similar differential expression patterns can be assigned to Groups. At least two Groups were identified, and are described below.

Group 1

Genes That Exhibit Differential Expression in Colon Cancer in a Pattern that Correlates with IGF2

Using both the Student-t test and the Spearman rank correlation test, the differential expression data of IGF2 correlated with that of 14 distinct genes: TTK, MAPKAPK2, MARCKS, BBS2, CETN2 CGI-148 protein, FGFR4, FHL3, FLJ22066, KIP2, MGC:29604, NQO2, and OGG1 (see Table 12). The differential expression data for these genes is presented in graphical form in FIGS. 2-17. This group was identified as Group 1. IGF2 is a secreted protein and has been reported to be involved in colon as well as other cancers (Toretsky J A and Helman L J (1996) J Endocrinol 149(3):367-72). Genes whose expression patterns correlate with IGF2 may provide a mechanism for the involvement of IGF2 in cancer. Among the genes in Group 1 are genes such as TTK (a kinase implicated in mitotic spindle check point), MAP-KAP kinase 2 (mitogen-activated protein (MAP) kinase activated protein kinase 2), and MARCKS (myristoylated alanine-rich C kinase substrate, which is a substrate of protein kinase C). The protein products of these genes and their associated signaling pathways can be targets for small molecule drug development for anti-cancer therapy. Furthermore, the upregulation of IGF2 can be a criterion for selecting patients who will benefit from anti-cancer therapy targeted to the genes in Group 1 and their associated pathway components.

Group 2

Genes that Exhibit Differential Expression in Colon Cancer in a Pattern that Correlates Interferon Induced Transmembrane (IFITM) Protein Family

Using the Spearman rank correlation test, the differential expression data of the IFITM family (1-8U; 1-8D; 9-27) correlated with that of 2 other genes: ITAK and BIRC3/H-IAP1 (see Table 12). The differential expression data for these genes is presented in graphical form in FIGS. 18-21. This group was identified as Group 2. 1-8U/IFITM3 was previously reported as a gene differentially upregulated in ulcerative-colitis-associated colon cancer (Hisamatsu et al (1999) Cancer Research 59, 5927-5931). Genes whose expression patterns correlate with 1-8U/IFITM3 and its family members may provide a mechanism for the involvement of inflammation in colon cancer. There are at least 3 members of the IFITM family: 9-27/IFITM1, 1-8D/IFITM2 and 1-8U/IFITM3. The polynucleotides used for the detection of 1-8U/IFITM3 are within a domain that is highly conserved among the 3 members. Therefore, the upregulation detected by the corresponding microarray spots may indicate the upregulation of one or multiple members within the family. Among the genes in Group 2 are ITAK (IL-1, TNF alpha activated kinase) and BIRC3/H-IAP1 (human inhibitor of apoptosis 1). The protein products of these genes and their associated signaling pathways can be targets for small molecule drug development for anti-cancer therapy. Furthermore, the upregulation of the IFITM can be a criterion for selecting patients who will benefit from anti-cancer therapy targeted to the genes in Group 2 and their associated pathway components.

Example 12 Antisense Regulation of Gene Expression

The expression of the differentially expressed genes represented by the polynucleotides in the cancerous cells can be analyzed using antisense knockout technology to confirm the role and function of the gene product in tumorigenesis, e.g., in promoting a metastatic phenotype.

A number of different oligonucleotides complementary to the mRNA generated by the differentially expressed genes identified herein can be designed as potential antisense oligonucleotides, and tested for their ability to suppress expression of the genes. Sets of antisense oligomers specific to each candidate target are designed using the sequences of the polynucleotides corresponding to a differentially expressed gene and the software program HYBsimulator Version 4 (available for Windows 95/Windows NT or 5 for Power Macintosh, RNAture, Inc. 1003 Health Sciences Road, West, Irvine, Calif. 92612 USA). Factors that are considered when designing antisense oligonucleotides include: 1) the secondary structure of oligonucleotides; 2) the secondary structure of the target gene; 3) the specificity with no or minimum cross-hybridization to other expressed genes; 4) stability; 5) length and 6) terminal GC content. The antisense oligonucleotide is designed so that it will hybridize to its target sequence under conditions of high stringency at physiological temperatures (e.g., an optimal temperature for the cells in culture to provide for hybridization in the cell, e.g., about 37° C.), but with minimal formation of homodimers.

Using the sets of oligomers and the HYBsimulator program, three to ten antisense oligonucleotides and their reverse controls are designed and synthesized for each candidate mRNA transcript, which transcript is obtained from the gene corresponding to the target polynucleotide sequence of interest. Once synthesized and quantitated, the oligomers are screened for efficiency of a transcript knock-out in a panel of cancer cell lines. The efficiency of the knock-out is determined by analyzing mRNA levels using lightcycler quantification. The oligomers that resulted in the highest level of transcript knock-out, wherein the level was at least about 50%, preferably about 80-90%, up to 95% or more up to undetectable message, are selected for use in a cell-based proliferation assay, an anchorage independent growth assay, and an apoptosis assay.

The ability of each designed antisense oligonucleotide to inhibit gene expression is tested through transfection into SW620 colon carcinoma cells. For each transfection mixture, a carrier molecule (such as a lipid, lipid derivative, lipid-like molecule, cholesterol, cholesterol derivative, or cholesterol-like molecule) is prepared to a working concentration of 0.5 mM in water, sonicated to yield a uniform solution, and filtered through a 0.45 μm PVDF membrane. The antisense or control oligonucleotide is then prepared to a working concentration of 100 μM in sterile Millipore water. The oligonucleotide is further diluted in OptiMEM™ (Gibco/BRL), in a microfuge tube, to 2 μM, or approximately 20 μg oligo/ml of OptiMEM™. In a separate microfuge tube, the carrier molecule, typically in the amount of about 1.5-2 nmol carrier/μg antisense oligonucleotide, is diluted into the same volume of OptiMEM™ used to dilute the oligonucleotide. The diluted antisense oligonucleotide is immediately added to the diluted carrier and mixed by pipetting up and down. Oligonucleotide is added to the cells to a final concentration of 30 nM.

The level of target mRNA that corresponds to a target gene of interest in the transfected cells is quantitated in the cancer cell lines using the Roche LightCycler™ real-time PCR machine. Values for the target mRNA are normalized versus an internal control (e.g., beta-actin). For each 20 μl reaction, extracted RNA (generally 0.2-1 μg total) is placed into a sterile 0.5 or 1.5 ml microcentrifuge tube, and water is added to a total volume of 12.5 μl. To each tube is added 7.5 μl of a buffer/enzyme mixture, prepared by mixing (in the order listed) 2.5 μl H₂O, 2.0 μl 10× reaction buffer, 10 μl oligo dT (20 pmol), 1.0 μl dNTP mix (10 mM each), 0.5 μl RNAsin® (20 u) (Ambion, Inc., Hialeah, Fla.), and 0.5 μl MMLV reverse transcriptase (50 u) (Ambion, Inc.). The contents are mixed by pipetting up and down, and the reaction mixture is incubated at 42° C. for 1 hour. The contents of each tube are centrifuged prior to amplification.

An amplification mixture is prepared by mixing in the following order: 1× PCR buffer II, 3 mM MgCl₂, 140 μM each dNTP, 0.175 pmol each oligo, 1:50,000 dil of SYBR® Green, 0.25 mg/ml BSA, 1 unit Taq polymerase, and H₂O to 20 μl. (PCR buffer II is available in 10× concentration from Perkin-Elmer, Norwalk, Conn.). In 1× concentration it contains 10 mM Tris pH 8.3 and 50 mM KCl. SYBR® Green (Molecular Probes, Eugene, Oreg.) is a dye which fluoresces when bound to double stranded DNA. As double stranded PCR product is produced during amplification, the fluorescence from SYBR® Green increases. To each 20 μl aliquot of amplification mixture, 2 μl of template RT is added, and amplification is carried out according to standard protocols. The results are expressed as the percent decrease in expression of the corresponding gene product relative to non-transfected cells, vehicle-only transfected (mock-transfected) cells, or cells transfected with reverse control oligonucleotides.

Example 13 Effect of Expression on Proliferation

The effect of gene expression on the inhibition of cell proliferation can be assessed in metastatic breast cancer cell lines (MDA-MB-231 (“231”)); SW620 colon colorectal carcinoma cells; SKOV3 cells (a human ovarian carcinoma cell line); or LNCaP, PC3, 22Rv1, MDA-PCA-2b, or DU145 prostate cancer cells.

Cells are plated to approximately 60-80% confluency in 96-well dishes. Antisense or reverse control oligonucleotide is diluted to 2 μM in OptiMEM™. The oligonucleotide-OptiMEM™ can then be added to a delivery vehicle, which delivery vehicle can be selected so as to be optimized for the particular cell type to be used in the assay. The oligo/delivery vehicle mixture is then further diluted into medium with serum on the cells. The final concentration of oligonucleotide for all experiments can be about 300 nM.

Antisense oligonucleotides are prepared as described above (see Example 12). Cells are transfected overnight at 37° C. and the transfection mixture is replaced with fresh medium the next morning. Transfection is carried out as described above in Example 12.

Those antisense oligonucleotides that result in inhibition of proliferation of SW620 cells indicate that the corresponding gene plays a role in production or maintenance of the cancerous phenotype in cancerous colon cells. Those antisense oligonucleotides that inhibit proliferation in SKOV3 cells represent genes that play a role in production or maintenance of the cancerous phenotype in cancerous breast cells. Those antisense oligonucleotides that result in inhibition of proliferation of MDA-MB-231 cells indicate that the corresponding gene plays a role in production or maintenance of the cancerous phenotype in cancerous ovarian cells. Those antisense oligonucleotides that inhibit proliferation in LNCaP, PC3, 22Rvl, MDA-PCA-2b, or DU145 cells represent genes that play a role in production or maintenance of the cancerous phenotype in cancerous prostate cells.

Example 14 Effect of Gene Expression on cell Migration

The effect of gene expression on the inhibition of cell migration can be assessed in SW620 colon cancer cells using static endothelial cell binding assays, non-static endothelial cell binding assays, and transmigration assays.

For the static endothelial cell binding assay, antisense oligonucleotides are prepared as described above (see Example 12). Two days prior to use, colon cancer cells (CaP) are plated and transfected with antisense oligonucleotide as described above (see Examples 4 and 5). On the day before use, the medium is replaced with fresh medium, and on the day of use, the medium is replaced with fresh medium containing 2 μM CellTracker green CMFDA (Molecular Probes, Inc.) and cells are incubated for 30 min. Following incubation, CaP medium is replaced with fresh medium (no CMFDA) and cells are incubated for an additional 30-60 min. CaP cells are detached using CMF PBS/2.5 mM EDTA or trypsin, spun and resuspended in DMEM/1% BSA/10 mM HEPES pH 7.0. Finally, CaP cells are counted and resuspended at a concentration of 1×10⁶ cells/ml.

Endothelial cells (EC) are plated onto 96-well plates at 40-50% confluence 3 days prior to use. On the day of use, EC are washed 1× with PBS and 50λ DMDM/1%BSA/10mM HEPES pH 7 is added to each well. To each well is then added 50K (50□) CaP cells in DMEM/1% BSA/10 mM HEPES pH 7. The plates are incubated for an additional 30 min and washed 5× with PBS containing Ca⁺⁺ and Mg⁺⁺. After the final wash, 100 μL PBS is added to each well and fluorescence is read on a fluorescent plate reader (Ab492/Em 516 nm).

For the non-static endothelial cell binding assay, CaP are prepared as described above. EC are plated onto 24-well plates at 30-40% confluence 3 days prior to use. On the day of use, a subset of EC are treated with cytokine for 6 hours then washed 2× with PBS. To each well is then added 150-200K CaP cells in DMEM/1% BSA/10 mM HEPES pH 7. Plates are placed on a rotating shaker (70 RPM) for 30 min and then washed 3× with PBS containing Ca⁺⁺ and Mg⁺⁺. After the final wash, 500 μL PBS is added to each well and fluorescence is read on a fluorescent plate reader (Ab492/Em 516 nm).

For the transmigration assay, CaP are prepared as described above with the following changes. On the day of use, CaP medium is replaced with fresh medium containing 5 μM CellTracker green CMFDA (Molecular Probes, Inc.) and cells are incubated for 30 min. Following incubation, CaP medium is replaced with fresh medium (no CMFDA) and cells are incubated for an additional 30-60 min. CaP cells are detached using CMF PBS/2.5 mM EDTA or trypsin, spun and resuspended in EGM-2-MV medium. Finally, CaP cells are counted and resuspended at a concentration of 1×10⁶ cells/ml.

EC are plated onto FluorBlok transwells (BD Biosciences) at 30-40% confluence 5-7 days before use. Medium is replaced with fresh medium 3 days before use and on the day of use. To each transwell is then added 50K labeled CaP. 30 min prior to the first fluorescence reading, 10 μg of FITC-dextran (10K MW) is added to the EC plated filter. Fluorescence is then read at multiple time points on a fluorescent plate reader (Ab492/Em 516 nm).

Those antisense oligonucleotides that result in inhibition of binding of SW620 colon cancer cells to endothelial cells indicate that the corresponding gene plays a role in the production or maintenance of the cancerous phenotype in cancerous colon cells. Those antisense oligonucleotides that result in inhibition of endothelial cell transmigration by SW620 colon cancer cells indicate that the corresponding gene plays a role in the production or maintenance of the cancerous phenotype in cancerous colon cells.

Example 15 Effect of Gene Expression on Colony Formation

The effect of gene expression upon colony formation of SW620 cells, SKOV3 cells, MD-MBA-231 cells, LNCaP cells, PC3 cells, 22Rvl cells, MDA-PCA-2b cells, and DU145 cells can be tested in a soft agar assay. Soft agar assays are conducted by first establishing a bottom layer of 2 ml of 0.6% agar in media plated fresh within a few hours of layering on the cells. The cell layer is formed on the bottom layer by removing cells transfected as described above from plates using 0.05% trypsin and washing twice in media. The cells are counted in a Coulter counter, and resuspended to 10⁶ per ml in media. 10 μl aliquots are placed with media in 96-well plates (to check counting with WST1), or diluted further for the soft agar assay. 2000 cells are plated in 800 μl 0.4% agar in duplicate wells above 0.6% agar bottom layer. After the cell layer agar solidifies, 2 ml of media is dribbled on top and antisense or reverse control oligo (produced as described in Example 12) is added without delivery vehicles. Fresh media and oligos are added every 3-4 days. Colonies form in 10 days to 3 weeks. Fields of colonies are counted by eye. Wst-1 metabolism values can be used to compensate for small differences in starting cell number. Larger fields can be scanned for visual record of differences.

Those antisense oligonucleotides that result in inhibition of colony formation of SW620 cells indicate that the corresponding gene plays a role in production or maintenance of the cancerous phenotype in cancerous colon cells. Those antisense oligonucleotides that inhibit colony formation in SKOV3 cells represent genes that play a role in production or maintenance of the cancerous phenotype in cancerous breast cells. Those antisense oligonucleotides that result in inhibition of colony formation of MDA-MB-231 cells indicate that the corresponding gene plays a role in production or maintenance of the cancerous phenotype in cancerous ovarian cells. Those antisense oligonucleotides that inhibit colony formation in LNCaP, PC3, 22Rvl, MDA-PCA-2b, or DU145 cells represent genes-that play a role in production or maintenance of the cancerous phenotype in cancerous prostate cells.

Example 16 Induction of Cell Death Upon Depletion of Polypeptides by Depletion of mRNA (“Antisense Knockout”)

In order to assess the effect of depletion of a target message upon cell death, SW620 cells, or other cells derived from a cancer of interest, can be transfected for proliferation assays. For cytotoxic effect in the presence of cisplatin (cis), the same protocol is followed but cells are left in the presence of 2 μM drug. Each day, cytotoxicity is monitored by measuring the amount of LDH enzyme released in the medium due to membrane damage. The activity of LDH is measured using the Cytotoxicity Detection Kit from Roche Molecular Biochemicals. The data is provided as a ratio of LDH released in the medium vs. the total LDH present in the well at the same time point and treatment (rLDH/tLDH). A positive control using antisense and reverse control oligonucleotides for BCL2 (a known anti-apoptotic gene) is included; loss of message for BCL2 leads to an increase in cell death compared with treatment with the control oligonucleotide (background cytotoxicity due to transfection).

Example 17 Functional Analysis Gene Products Differentially Expressed in Colon Cancer Patients

The gene products of sequences of a gene differentially expressed in cancerous cells can be further analyzed to confirm the role and function of the gene product in tumorigenesis, e.g., in promoting or inhibiting development of a metastatic phenotype. For example, the function of gene products corresponding to genes identified herein can be assessed by blocking function of the gene products in the cell. For example, where the gene product is secreted or associated with a cell surface membrane, blocking antibodies can be generated and added to cells to examine the effect upon the cell phenotype in the context of, for example, the transformation of the cell to a cancerous, particularly a metastatic, phenotype. In order to generate antibodies, a clone corresponding to a selected gene product is selected, and a sequence that represents a partial or complete coding sequence is obtained. The resulting clone is expressed, the polypeptide produced isolated, and antibodies generated. The antibodies are then combined with cells and the effect upon tumorigenesis assessed.

Where the gene product of the differentially expressed genes identified herein exhibits sequence homology to a protein of known function (e.g., to a specific kinase or protease) and/or to a protein family of known function (e.g., contains a domain or other consensus sequence present in a protease family or in a kinase family), then the role of the gene product in tumorigenesis, as well as the activity of the gene product, can be examined using small molecules that inhibit or enhance function of the corresponding protein or protein family.

Additional functional assays include, but are not necessarily limited to, those that analyze the effect of expression of the corresponding gene upon cell cycle and cell migration. Methods for performing such assays are well known in the art.

Example 18 Contig Assembly and Additional Gene Characterization

The sequences of the polynucleotides provided in the present invention can be used to extend the sequence information of the gene to which the polynucleotides correspond (e.g., a gene, or mRNA encoded by the gene, having a sequence of the polynucleotide described herein). This expanded sequence information can in turn be used to further characterize the corresponding gene, which in turn provides additional information about the nature of the gene product (e.g., the normal function of the gene product). The additional information can serve to provide additional evidence of the gene product's use as a therapeutic target, and provide further guidance as to the types of agents that can modulate its activity.

In one example, a contig is assembled using a sequence of a polynucleotide of the present invention, which is present in a clone. A “contig” is a contiguous sequence of nucleotides that is assembled from nucleic acid sequences having overlapping (e.g., shared or substantially similar) sequence information. The sequences of publicly-available ESTs (Expressed Sequence Tags) and the sequences of various clones from several cDNA libraries synthesized at Chiron can be used in the contig assembly.

The contig is assembled using the software program Sequencher, version 4.05, according to the manufacturer's instructions and an overview alignment of the contiged sequences is produced. The sequence information obtained in the contig assembly can then be used to obtain a consensus sequence derived from the contig using the Sequencher program. The consensus sequence is used as a query sequence in a TeraBLASTN search of the DGTI DoubleTwist-Gene Index (DoubleTwist, Inc., Oakland, Calif.), which contains all the EST and non-redundant sequence in public databases.

Through contig assembly and the use of homology searching software programs, the sequence information provided herein can be readily extended to confirm, or confirm a predicted, gene having the sequence of the polynucleotides described in the present invention. Further the information obtained can be used to identify the function of the gene product of the gene corresponding to the polynucleotides described herein. While not necessary to the practice of the invention, identification of the function of the corresponding gene, can provide guidance in the design of therapeutics that target the gene to modulate its activity and modulate the cancerous phenotype (e.g., inhibit metastasis, proliferation, and the like).

Example 19 Source of Biological Materials

The biological materials used in the experiments that led to the present invention are described below.

Source of Patient Tissue Samples

Normal and cancerous tissues were collected from patients using laser capture microdisection (LCM) techniques, which techniques are well known in the art (see, e.g., Ohyama et al. (2000) Biotechniques 29:530-6; Curran et al. (2000) Mol. Pathol. 53:64-8; Suarez-Quian et al. (1999) Biotechniques 26:328-35; Simone et al. (1998) Trends Genet 14:272-6; Conia et al. (1997) J. Clin. Lab. Anal. 11:28-38; Emmert-Buck et al. (1996) Science 274:998-1001). Table 13 below provides information about each patient from which the prostate tissue samples were isolated, including: 1) the “Patient ID”, which is a number assigned to the patient for identification purposes; 2) the “Tissue Type”; and 3) the “Gleason Grade” of the tumor. Hisopathology of all primary tumors indicated the tumor was adenocarcinoma. TABLE 13 Prostate patient data. Gleason Patient ID Tissue Type Grade 93 Prostate Cancer 3 + 4 94 Prostate Cancer 3 + 3 95 Prostate Cancer 3 + 3 96 Prostate Cancer 3 + 3 97 Prostate Cancer 3 + 2 100 Prostate Cancer 3 + 3 101 Prostate Cancer 3 + 3 104 Prostate Cancer 3 + 3 105 Prostate Cancer 3 + 4 106 Prostate Cancer 3 + 3 138 Prostate Cancer 3 + 3 151 Prostate Cancer 3 + 3 153 Prostate Cancer 3 + 3 155 Prostate Cancer 4 + 3 171 Prostate Cancer 3 + 4 173 Prostate Cancer 3 + 4 231 Prostate Cancer 3 + 4 232 Prostate Cancer 3 + 3 251 Prostate Cancer 3 + 4 282 Prostate Cancer 4 + 3 286 Prostate Cancer 3 + 3 294 Prostate Cancer 3 + 4 351 Prostate Cancer 5 + 4 361 Prostate Cancer 3 + 3 362 Prostate Cancer 3 + 3 365 Prostate Cancer 3 + 2 368 Prostate Cancer 3 + 3 379 Prostate Cancer 3 + 4 388 Prostate Cancer 5 + 3 391 Prostate Cancer 3 + 3 420 Prostate Cancer 3 + 3 425 Prostate Cancer 3 + 3 428 Prostate Cancer 4 + 3 431 Prostate Cancer 3 + 4 492 Prostate Cancer 3 + 3 493 Prostate Cancer 3 + 4 496 Prostate Cancer 3 + 3 510 Prostate Cancer 3 + 3 511 Prostate Cancer 4 + 3 514 Prostate Cancer 3 + 3 549 Prostate Cancer 3 + 3 552 Prostate Cancer 3 + 3 858 Prostate Cancer 3 + 4 859 Prostate Cancer 3 + 4 864 Prostate Cancer 3 + 4 883 Prostate Cancer 4 + 4 895 Prostate Cancer 3 + 3 901 Prostate Cancer 3 + 3 909 Prostate Cancer 3 + 3 921 Prostate Cancer 3 + 3 923 Prostate Cancer 4 + 3 934 Prostate Cancer 3 + 3 1134 Prostate Cancer 3 + 4 1135 Prostate Cancer 3 + 3 1136 Prostate Cancer 3 + 4 1137 Prostate Cancer 3 + 3 1138 Prostate Cancer 4 + 3

Source of Polynucleotides on Arrays

Polynucleotides for use on the arrays were obtained from both publicly available sources and from cDNA libraries generated from selected cell lines and patient tissues. Table 14 provides information about the polynucleotides on the arrays including: 1) the “SEQ ID NO” assigned to each sequence for use in the present specification; 2) the spot identification number (“Spot ID”), an internal reference that serves as a unique identifier for the spot on the array; 3) the “Sequence Name” assigned to each sequence; and 4) the “Sample Name or Clone Name” assigned to the sample or clone from which the sequence was isolated. The sequences corresponding to the SEQ ID NOS are provided in the Sequence Listing.

Characterization of Sequences

The sequences of the isolated polynucleotides were first masked to eliminate low complexity sequences using the RepeatMasker masking program, publicly available through a web site supported by the University of Washington (See also Smit, A. F. A. and Green, P., unpublished results). Generally, masking does not influence the final search results, except to eliminate sequences of relative little interest due to their low complexity, and to eliminate multiple “hits” based on similarity to repetitive regions common to multiple sequences, e.g., Alu repeats. Masking resulted in the elimination of several sequences.

The remaining sequences of the isolated polynucleotides were used in a homology search of the GenBank database using the TeraBLAST program (TimeLogic, Crystal Bay, Nev.), a DNA and protein sequence homology searching algorithm. TeraBLAST is a version of the publicly available BLAST search algorithm developed by the National Center for Biotechnology, modified to operate at an accelerated speed with increased sensitivity on a specialized computer hardware platform. The program was run with the default parameters recommended by TimeLogic to provide the best sensitivity and speed for searching DNA and protein sequences. Gene assignment for the query sequences was determined based on best hit form the GenBank database; expectancy values are provided with the hit.

Summary of TeraBLAST Search Results

Tables 15 and 16 provide information about the gene corresponding to each polynucleotide. Tables 15 and 16 include: 1) the spot identification number (“Spot ID”); 2) the GenBank Accession Number of the publicly available sequence corresponding to the polynucleotide (“GenBankHit”); 3) a description of the GenBank sequence (“GenBankDesc”); and 4) the score of the similarity of the polynucleotide sequence and the GenBank sequence (“GenBankScore”). The published information for each GenBank and EST description, as well as the corresponding sequence identified by the provided accession number, are incorporated herein by reference.

Example 20 Detection of Differential Expression Using Arrays

cDNA probes were prepared from total RNA isolated from the patient cells described above. Since LCM provides for the isolation of specific cell types to provide a substantially homogenous cell sample, this provided for a similarly pure RNA sample.

Total RNA was first reverse transcribed into cDNA using a primer containing a T7 RNA polymerase promoter, followed by second strand DNA synthesis. cDNA was then transcribed in vitro to produce antisense RNA using the T7 promoter-mediated expression (see, e.g., Luo et al. (1999) Nature Med 5:117-122), and the antisense RNA was then converted into cDNA. The second set of cDNAs were again transcribed in vitro, using the T7 promoter, to provide antisense RNA. Optionally, the RNA was again converted into cDNA, allowing for up to a third round of T7-mediated amplification to produce more antisense RNA. Thus the procedure provided for two or three rounds of in vitro transcription to produce the final RNA used for fluorescent labeling.

Fluorescent probes were generated by first adding control RNA to the antisense RNA mix, and producing fluorescently labeled cDNA from the RNA starting material. Fluorescently labeled cDNAs prepared from the tumor RNA sample were compared to fluorescently labeled cDNAs prepared from normal cell RNA sample. For example, the cDNA probes from the normal cells were labeled with Cy3 fluorescent dye (green) and the cDNA probes prepared from the tumor cells were labeled with Cy5 fluorescent dye (red), and vice versa.

Each array used had an identical spatial layout and control spot set. Each microarray was divided into two areas, each area having an array with, on each half, twelve groupings of 32×12 spots, for a total of about 9,216 spots on each array. The two areas are spotted identically which provide for at least two duplicates of each clone per array.

Polynucleotides for use on the arrays were obtained from both publicly available sources and from cDNA libraries generated from selected cell lines and patient tissues as described above and in Table 14. PCR products of from about 0.5 kb to 2.0 kb amplified from these sources were spotted onto the array using a Molecular Dynamics Gen III spotter according to the manufacturer's recommendations. The first row of each of the 24 regions on the array had about 32 control spots, including 4 negative control spots and 8 test polynucleotides. The test polynucleotides were spiked into each sample before the labeling reaction with a range of concentrations from 2-600 pg/slide and ratios of 1:1. For each array design, two slides were hybridized with the test samples reverse-labeled in the labeling reaction. This provided for about four duplicate measurements for each clone, two of one color and two of the other, for each sample.

The differential expression assay was performed by mixing equal amounts of probes from tumor cells and normal cells of the same patient. The arrays were prehybridized by incubation for about 2 hrs at 60° C. in 5×SSC/0.2% SDS/1 mM EDTA, and then washed three times in water and twice in isopropanol. Following prehybridization of the array, the probe mixture was then hybridized to the array under conditions of high stringency (overnight at 42° C. in 50% formamide, 5×SSC, and 0.2% SDS. After hybridization, the array was washed at 55° C. three times as follows: 1) first wash in 1×SSC/0.2% SDS; 2) second wash in 0.1×SSC/0.2% SDS; and 3) third wash in 0.1×SSC.

The arrays were then scanned for green and red fluorescence using a Molecular Dynamics Generation III dual color laser-scanner/detector. The images were processed using BioDiscovery Autogene software, and the data from each scan set normalized to provide for a ratio of expression relative to normal. Data from the microarray experiments was analyzed according to the algorithms described in U.S. application Ser. No. 60/252,358, filed Nov. 20, 2000, by E. J. Moler, M. A. Boyle, and F. M. Randazzo, and entitled “Precision and accuracy in cDNA microarray data,” which application is specifically incorporated herein by reference.

The experiment was repeated, this time labeling the two probes with the opposite color in order to perform the assay in both “color directions.” Each experiment was sometimes repeated with two more slides (one in each color direction). The level fluorescence for each sequence on the array expressed as a ratio of the geometric mean of 8 replicate spots/genes from the four arrays or 4 replicate spots/gene from 2 arrays or some other permutation. The data were normalized using the spiked positive controls present in each duplicated area, and the precision of this normalization was included in the final determination of the significance of each differential. The fluorescent intensity of each spot was also compared to the negative controls in each duplicated area to determine which spots have detected significant expression levels in each sample.

A statistical analysis of the fluorescent intensities was applied to each set of duplicate spots to assess the precision and significance of each differential measurement, resulting in a p-value testing the null hypothesis that there is no differential in the expression level between the tumor and normal samples of each patient. During initial analysis of the microarrays, the hypothesis was accepted if p>10⁻³, and the differential ratio was set to 1.000 for those spots. All other spots have a significant difference in expression between the tumor and normal sample. If the tumor sample has detectable expression and the normal does not, the ratio is truncated at 1000 since the value for expression in the normal sample would be zero, and the ratio would not be a mathematically useful value (e.g., infinity). If the normal sample has detectable expression and the tumor does not, the ratio is truncated to 0.001, since the value for expression in the tumor sample would be zero and the ratio would not be a mathematically useful value. These latter two situations are referred to herein as “on/off.” Database tables were populated using a 95% confidence level (p>0.05). TABLE 14 SEQ ID Spot NO Id Sequence Name Sample Name or Clone Name 342 987 gbH13036.1 NIH50_43563 343 1016 019.G8.sp6_128478 M00006968D:E03 344 1019 1chip1.K15.T7HSQ3_328869 M00005636D:B08 345 1033 RTA00000184AR.p.16.1 M00001568C:D03 346 1047 122.B4.sp6_132088 M00001655C:E04 347 1049 324.E8.sp6_145687 M00001657A:C02 348 149 4chip1.F13.SP6_329984 M00001470A:C06 349 260 HX2105-6 2105-6 350 279 gbR51346.1 NIH50_39093 351 283 gbH05914.1 NIH50_43550 352 315 1chip1.K13.T7HSQ3_328837 M00005629C:E09 353 320 1chip1.P13.T7HSQ3_328842 M00006964D:C05 354 342 626.C7.sp6_157434 M00007965A:C03 355 369 SL178m13 SL178 356 403 RTA00000848F.c.07.1 M00023298C:E11 357 453 3chip1.F02.T7HSQ3_329424 M00008050A:D12 358 460 40000063.F01.T7HSQ3_332264 M00022135A:C04 359 462 642.G1.sp6_156335 M00022137A:A05 360 507 RTA00000603F.b.03.1 M00004163D:A08 361 511 774.H7.sp6_162527 M00004167D:H05 362 515 627.B2.sp6_157609 M00007976D:D10 363 530 636.A2.sp6_158173 M00022004A:F05 364 578 271.A1.sp6_145248 M00001429A:G04 365 579 269.B1.sp6_144876 M00001358B:F05 366 582 271.C1.sp6_145272 M00001429C:C03 367 589 269.G1.sp6_144936 M00001360C:B05 368 596 271.B7.sp6_145266 M00001445D:D07 369 605 6chip1.N13.SP6_330760 M00001374D:D10 370 627 8chip1.C14.Topo2_336359 2016-5 371 635 HX2058-2 2058-2 372 637 HX2090-1 2090-1 373 641 1chip1.A02.T7HSQ3_328651 M00006600A:E02 374 653 RTA00000321F.e.05.1 M00006619A:C04 375 656 959.SP6.H01_180102 M00007082B:D06 376 688 RTA00001082F.m.03.1 M00027211C:F06 377 742 660.C2.sp6_159543 M00026921D:F12 378 760 6chip1.G15.SP6_330785 M00026961D:G06 379 764 RTA00001069F.i.01.1 M00026962D:E01 380 770 021.A2.sp6_128760 M00005467A:G06 381 784 021.H2.sp6_128844 M00007007A:H06 382 789 5chip1.E16.SP6_330415 M00001393B:B01 383 816 40000062.H02.T7HSQ3_332178 M00008095B:G07 384 828 634.F8.sp6_155946 M00021638B:F03 385 866 RTA22200231F.p.10.1.P M00008002B:G03 386 920 656.D8.sp6_159369 M00026896A:C09 387 929 919.A2.SP6_168666 M00001339C:G05 388 964 HX2106-1 2106-1 389 978 HX2103-1 2103-1 390 1061 8chip1.E03.Topo2_336185 SL141 391 1108 661.B8.sp6_159729 M00027116A:A10 392 1111 RTA00001069F.b.02.1 M00023302D:E10 393 1117 653.G8.sp6_159021 M00023305A:C02 394 1137 022.A6.sp6_128956 M00007943C:f02 395 1145 019.G8.sp6_128478 M00006968D:e03 396 1176 642.D8.sp6_156306 M00022180D:E11 397 1195 5chip1.K03.SP6_330213 M00001675B:G05 398 1251 RTA00001038F.a.21.1 M00023413D:F04 399 1261 655.G2.sp6_156528 M00023419C:B06 400 1266 RTA00000922F.g.12.1 M00026900D:F02 401 1282 271.A2.sp6_145249 M00001430D:H07 402 1283 6chip1.D03.SP6_330590 M00001360D:H10 403 1298 RTA00000585F.o.09.2 M00001448A:C04 404 1307 269.F8.sp6_144931 M00001378D:E03 405 1309 269.G8.sp6_144943 M00001378D:G05 406 1310 271.G8.sp6_145327 M00001451D:F01 407 1319 HX2030-2 2030-2 408 1323 8chip1.K04.Topo2_336207 2054-2 409 1325 HX2076-5 2076-5 410 1331 HX2017-1 2017-1 411 1341 HX2090-3 2090-3 412 1351 1chip1.G04.T7HSQ3_328689 M00006630A:D01 413 1466 RTA00000852F.h.21.1 M00026964B:H10 414 1506 40000062.A03.T7HSQ3_332179 M00008095C:A10 415 1524 40000062.B09.T7HSQ3_332228 M00021649B:F09 416 1607 323.D3.sp6_145478 M00001497A:A09 417 1644 020.A2.sp6_128592 M00001393B:B01 418 1645 919.G3.SP6_168739 M00001342C:C01 419 1659 268.F9.sp6_144740 M00001350B:D10 420 1663 919.H9.SP6_168757 M00001350C:C05 421 1664 270.H9.sp6_145148 M00001411A:G02 422 1689 gbR61053.1 NIH50_42096 423 1693 gbH16957.1 NIH50_50117 424 1723 1chip1.K17.T7HSQ3_328901 M00005694A:A09 425 1752 626.D9.sp6_157448 M00007967D:G06 426 1767 SL149m13 SL149 427 1769 8chip1.I05.Topo2_336221 SL150 428 1789 8chip1.M17.Topo2_336417 SL200 429 1791 SL201m13 SL201 430 1794 661.A3.sp6_159712 M00027028A:A06 431 1807 653.H3.sp6_159028 M00023285D:C05 432 1810 RTA00001069F.k.22.1 M00027143D:E10 433 1852 1chip1.L18.T7HSQ3_328918 M00005380A:E11 434 1859 3chip1.D06.T7HSQ3_329486 M00008057A:B01 435 1868 642.F3.sp6_156325 M00022151A:B12 436 1895 RTA22200222F.k.17.1.P M00004069B:G01 437 1899 RTA00000603F.a.21.1 M00004072D:E08 438 1927 RTA22200231F.l.22.1.P M00007985A:B08 439 1936 RTA00000854F.g.12.1 M00008020C:H09 440 1955 655.B3.sp6_156469 M00023423B:A04 441 1957 655.C3.sp6_156481 M00023424C:A01 442 1992 271.D3.sp6_145286 M00001434D:F08 443 2000 271.H3.sp6_145334 M00001435C:F08 444 2014 4chip1.M17.SP6_330055 M00001462A:E06 445 2028 8chip1.L06.Topo2_336240 2237-3 446 2030 8chip1.N06.Topo2_336242 2245-1 447 2067 1chip1.C18.T7HSQ3_328909 M00006715C:C09 448 2108 RTA00001083F.e.05.1 M00027619D:A06 449 2110 RTA00001083F.e.06.1 M00027622D:H04 450 2137 sl102t7 SL102 451 2139 sl103m13 SL103 452 2152 RTA22200241F.k.11.1.P M00026931B:E12 453 2190 021.G4.sp6_128834 M00006953B:C05 454 2237 3chip1.N19.T7HSQ3_329704 M00007943D:B09 455 2267 773.F10.sp6_162349 M00001573D:H09 456 2280 RTA00001206F.a.07.1 M00008023B:A05 457 2338 270.A4.sp6_145059 M00001394C:B12 458 2357 268.C10.sp6_144705 M00001351A:A01 459 2375 gbR35294.1 NIH50_37451 460 2381 gbH09589.1 NIH50_46171 461 2427 RTA00001064F.k.13.2 M00005767D:B03 462 2442 626.E4.sp6_157455 M00007960A:D12 463 2513 653.A10.sp6_158951 M00023312D:F10 464 2514 661.A10.sp6_159719 M00027168A:E01 465 2528 661.H10.sp6_159803 M00027176D:B08 466 2549 019.E10.sp6_128456 M00005645D:g06 467 2557 020.G4.sp6_128666 M00005404C:f02 468 2564 RTA22200232F.o.21.1.P M00022154C:D08 469 2568 642.D4.sp6_156302 M00022158D:C11 470 2588 642.F10.sp6_156332 M00022208D:B02 471 2605 774.G4.sp6_162502 M00004085C:C02 472 2613 774.C10.sp6_162546 M00004243D:C01 473 2621 RTA00000193AR.c.15.2 M00004248B:E08 474 2629 RTA22200231F.m.13.1.P M00007987B:F11 475 2632 RTA22200233F.c.14.1.P M00008025D:A02 476 2662 RTA00001069F.c.03.1 M00023363C:A04 477 2663 RTA00000786F.o.16.3 M00023431C:F07 478 2694 271.C4.sp6_145275 M00001436B:E11 479 2696 271.D4.sp6_145287 M00001436C:C03 480 2702 271.G4.sp6_145323 M00001437B:B08 481 2716 271.F10.sp6_145317 M00001468A:D02 482 2728 8chip1.H08.Topo2_336268 2208-5 483 2732 HX2237-4 2237-4 484 2734 HX2245-2 2245-2 485 2736 HX2254-2 2254-2 486 2751 HX2100-1 2100-1 487 2765 955.SP6.G04_177960 M00006653C:B09 488 2766 RTA22200230F.g.19.1.P M00007154B:H08 489 2791 RTA00000789F.g.11.1 M00003994A:G12 490 2837 sl108m13 SL108 491 2919 625.D5.sp6_155727 M00007936A:C09 492 2922 959.SP6.G09_180098 M00008100B:G11 493 2977 RTA22200231F.m.16.1.P M00007990D:A11 494 2979 RTA22200231F.m.20.1.P M00007992A:D02 495 2988 628.F9.sp6_157856 M00008039A:C09 496 3009 323.A5.sp6_145444 M00001503C:D01 497 3090 HX2104-3 2104-3 498 3091 gbR42581.1 NIH50_31143 499 3093 gbR45594.1 NIH50_35483 500 3097 gbR61295.1 NIH50_42352 501 3099 gbH05820.1 NIH50_44255 502 3101 gbH16908.1 NIH50_50666 503 3122 019.G10.sp6_128480 M00007019A:B01 504 3143 324.D5.sp6_145672 M00001605D:C02 505 3152 626.H5.sp6_157492 M00007963B:B04 506 3235 019.D5.sp6_128439 M00005443D:b03 507 3275 633.F5.sp6_156135 M00008072D:E12 508 3284 642.B11.sp6_156285 M00022211D:A02 509 3301 5chip1.E09.SP6_330303 M00003820A:G06 510 3317 774.C11.sp6_162554 M00004282B:D11 511 3346 636.A10.sp6_158181 M00022068C:F05 512 3372 RTA00000854F.m.01.1 M00023395C:F06 513 3394 271.A5.sp6_145252 M00001437D:E12 514 3396 271.B5.sp6_145264 M00001438A:B09 515 3419 269.F11.sp6_144934 M00001387A:A08 516 3440 HX2254-4 2254-4 517 3453 HX2093-3 2093-3 518 3455 HX2100-2 2100-2 519 3469 RTA00002902F.h.07.1.P M00006678A:A03 520 3517 RTA22200224F.j.03.1.P M00005358D:A11 521 3531 SL66t7 SL66 522 3575 654.D12.sp6_159181 M00023398C:D01 523 3683 RTA00000717F.o.13.1 M00007994C:F08 524 3710 RTA22200232F.i.18.1.P M00022074D:H11 525 3712 636.H11.sp6_158266 M00022075A:B09 526 3745 268.A6.sp6_144677 M00001344D:H07 527 3760 013717 M00001405B:A11 528 3772 270.F12.sp6_145127 M00001427D:G03 529 3776 270.H12.sp6_145151 M00001428C:A07 530 3785 gbR58991.1 NIH50_41452 531 3794 HX2105-1 2105-1 532 3831 1chip1.G23.T7HSQ3_328993 M00006582A:D11 533 4007 RTA22200222F.m.10.1.P M00004136A:D10 534 4019 774.B12.sp6_162561 M00004331A:A03 535 4037 RTA22200231F.o.10.1.P M00007996C:F04 536 4068 344.B6.sp6_146241 M00023397B:E08 537 4100 4chip1.C11.SP6_329949 M00001441A:A09 538 4107 920.F6.SP6_168826 M00001372A:D01 539 4123 019.A4.sp6_128402 M00001389A:F09 540 4124 4chip1.K23.SP6_330149 M00001481C:A12 541 4127 6chip1.P23.SP6_330922 M00001389C:G01 542 4128 4chip1.O23.SP6_330153 M00001482D:D11 543 4135 HX2032-2 2032-2 544 4157 HX2093-5 2093-5 545 4193 RTA00002895F.h.23.1.P M00004087B:E02 546 8454 2231168 I:2231168:08B01:C01 547 8486 1813269 I:1813269:05B01:C01 548 8509 1732092 I:1732092:05A01:G07 549 8513 Incyte3.A01.T3pINCY_352048 I:3325119:07A01:A01 550 8537 Incyte3.I13.T3pINCY_352248 I:3176222:07A01:E07 551 8546 Incyte2.B01.T3pINCY_351665 I:1705208:06B01:A01 552 8549 Incyte2.E01.T3pINCY_351668 I:1623214:06A01:C01 553 8568 Incyte2.H13.T3pINCY_351863 I:1712888:06B01:D07 554 8569 Incyte2.I13.T3pINCY_351864 I:1702752:06A01:E07 555 8570 1696224 I:1696224:06B01:E07 556 8599 Incyte5.H13.T3pINCY_353015 I:1678926:11A01:D07 557 8608 3676190 I:3676190:11B01:H07 558 8634 Incyt14.I13.T3pINCY_377264 I:1439934:03B01:E07 559 8637 1640555 I:1640555:03A01:G07 560 8644 Incyt12.C01.T3pINCY_368180 I:2171743:01B01:B01 561 8672 2885982 I:2885982:01B01:H07 562 8703 2917169 I:2917169:12A01:H07 563 8730 2477854 I:2477854:10B01:E07 564 8743 1858905 I:1858905:04A01:D01 565 8829 2950228 I:2950228:08A02:G07 566 8835 1732335 I:1732335:05A02:B01 567 8856 I1.H14.T3pINCY1_343720 I:1803418:05B02:D07 568 8858 I1.J14.T3pINCY1_343722 I:1857652:05B02:E07 569 8860 I1.L14.T3pINCY1_343724 I:1568725:05B02:F07 570 8862 I1.N14.T3pINCY1_343726 I:1687060:05B02:G07 571 8890 3044552 I:3044552:07B02:E07 572 8945 Incyte5.B14.T3pINCY_353025 I:3282436:11A02:A07 573 8959 1817388 I:1817388:11A02:H07 574 8960 Incyt10.O14.T3pINCY_367632 I:2488216:11B02:H07 575 8996 Incyt11.D02.T3pINCY_367813 I:2365149:01B02:B01 576 9008 Incyte8.P01.T3pINCY_354174 I:3211615:01B02:H01 577 9013 Incyte8.E14.T3pINCY_354371 I:1419396:01A02:C07 578 9021 Incyt11.N13.T3pINCY_367999 I:2862971:01A02:G07 579 9055 Incyte6.P13.T3pINCY_353598 I:4335824:12A02:H07 580 9082 3275493 I:3275493:10B02:E07 581 9097 2021576 I:2021576:04A02:E01 582 9110 Incyt14.F14.T3pINCY_377277 I:2989411:04B02:C07 583 9111 I1.G14.T3pINCY1_343719 I:1958902:04A02:D07 584 9143 2728590 I:2728590:02A02:D07 585 9168 Incyte4.O03.T3pINCY_352478 I:2344817:08B01:H02 586 9171 Incyte3.D16.T3pINCY_352291 I:3236109:08A01:B08 587 9186 1574890 I:1574890:05B01:A02 588 9191 1421929 I:1421929:05A01:D02 589 9201 3142736 I:3142736:05A01:A08 590 9278 Incyte2.N15.T3pINCY_351901 I:1305950:06B01:G08 591 9296 Incyt10.O03.T3pINCY_367456 I:1804548:11B01:H02 592 9300 Incyt10.C15.T3pINCY_367636 I:3053958:11B01:B08 593 9312 Incyt10.O15.T3pINCY_367648 I:2799347:11B01:H08 594 9318 Incyt14.E03.T3pINCY_377100 I:1312824:03B01:C02 595 9348 2745048 I:2745048:01B01:B02 596 9364 2683564 I:2683564:01B01:B08 597 9366 Incyt12.E15.T3pINCY_368406 I:2725511:01B01:C08 598 9368 Incyte8.H16.T3pINCY_354406 I:2233375:01B01:D08 599 9381 Incyt10.F03.T3pINCY_367447 I:3218334:12A01:C02 600 9442 I1.B03.T3pINCY1_343538 I:1636639:04B01:A02 601 9448 I1.H03.T3pINCY1_343544 I:2455617:04B01:D02 602 9456 I1.P03.T3pINCY1_343552 I:2806166:04B01:H02 603 9472 I1.P15.T3pINCY1_343744 I:2510171:04B01:H08 604 9487 Incyt12.O04.T3pINCY_368240 I:2190284:02A01:H02 605 9499 Incyte7.K15.T3pINCY_354009 I:1861971:02A01:F08 606 9501 3360454 I:3360454:02A01:G08 607 9512 2948256 I:2948256:08B02:D02 608 9527 2045705 I:2045705:08A02:D08 609 9528 2544622 I:2544622:08B02:D08 610 9540 1522716 I:1522716:05B02:B02 611 9552 I1.P04.T3pINCY1_343568 I:1820522:05B02:H02 612 9553 2365295 I:2365295:05A02:A08 613 9560 I1.H16.T3pINCY1_343752 I:1822577:05B02:D08 614 9574 2472778 I:2472778:07B02:C02 615 9596 3141918 I:3141918:07B02:F08 616 9618 1306814 I:1306814:06B02:A08 617 9624 Incyte2.H16.T3pINCY_351911 I:3034694:06B02:D08 618 9640 Incyt10.G04.T3pINCY_367464 I:2859033:11B02:D02 619 9645 Incyte5.N04.T3pINCY_352877 I:2795249:11A02:G02 620 9647 Incyte5.P04.T3pINCY_352879 I:2966535:11A02:H02 621 9649 Incyte5.B16.T3pINCY_353057 I:1483713:11A02:A08 622 9666 Incyt14.A04.T3pINCY_377112 I:1453049:03B02:A02 623 9678 Incyt14.M04.T3pINCY_377124 I:1415990:03B02:G02 624 9687 Incyte9.G15.T3pINCY_354773 I:2992851:03A02:D08 625 9697 Incyt11.B03.T3pINCY_367827 I:1477568:01A02:A02 626 9698 2779637 I:2779637:01B02:A02 627 9716 Incyt11.D16.T3pINCY_368037 I:2786575:01B02:B08 628 9720 Incyt11.H16.T3pINCY_368041 I:2455118:01B02:D08 629 9722 Incyt11.J16.T3pINCY_368043 I:2840251:01B02:E08 630 9739 2902903 I:2902903:12A02:F02 631 9741 Incyte6.N03.T3pINCY_353436 I:3126828:12A02:G02 632 9755 3126622 I:3126622:12A02:F08 633 9770 Incyte5.I04.T3pINCY_352872 I:2911347:10B02:E02 634 9884 Incyte4.K17.T3pINCY_352698 I:2908878:08B01:F09 635 9889 2639181 I:2639181:05A01:A03 636 9901 3132987 I:3132987:05A01:G03 637 9911 3139163 I:3139163:05A01:D09 638 9913 2242817 I:2242817:05A01:E09 639 9914 1904751 I:1904751:05B01:E09 640 9916 1750553 I:1750553:05B01:F09 641 9920 1888940 I:1888940:05B01:H09 642 9949 Incyte3.M17.T3pINCY_352316 I:3970665:07A01:G09 643 9952 Incyte3.P17.T3pINCY_352319 I:1633393:07B01:H09 644 9956 Incyte2.D05.T3pINCY_351731 I:1617326:06B01:B03 645 9981 Incyte2.M17.T3pINCY_351932 I:1720149:06A01:G09 646 9989 Incyte5.F05.T3pINCY_352885 I:2689747:11A01:C03 647 9995 Incyte5.L05.T3pINCY_352891 I:2367733:11A01:F03 648 10003 1850531 I:1850531:11A01:B09 649 10012 Incyt10.K17.T3pINCY_367676 I:2594407:11B01:F09 650 10020 Incyt14.C05.T3pINCY_377130 I:1406786:03B01:B03 651 10021 1930235 I:1930235:03A01:C03 652 10035 I1.C17.T3pINCY1_343763 I:1526240:03A01:B09 653 10046 Incyt14.M17.T3pINCY_377332 I:1510714:03B01:G09 654 10047 I1.O17.T3pINCY1_343775 I:2952864:03A01:H09 655 10083 2922292 I:2922292:12A01:B03 656 10103 Incyte6.G18.T3pINCY_353669 I:3714075:12A01:D09 657 10153 Incyt14.J05.T3pINCY_377137 I:1712592:04A01:E03 658 10160 I1.P05.T3pINCY1_343584 I:2696735:04B01:H03 659 10200 Incyte7.H17.T3pINCY_354038 I:1702266:02B01:D09 660 10231 1808121 I:1808121:08A02:D09 661 10243 Incyt15.C05.T3pINCY_377526 I:3070110:05A02:B03 662 10257 Incyt15.A17.T3pINCY_377716 I:2860815:05A02:A09 663 10285 Incyte3.M06.T3pINCY_352140 I:1930135:07A02:G03 664 10301 2669174 I:2669174:07A02:G09 665 10334 Incyte2.N18.T3pINCY_351949 I:3354893:06B02:G09 666 10355 Incyte5.D18.T3pINCY_353091 I:4215852:11A02:B09 667 10366 Incyt10.M18.T3pINCY_367694 I:2896792:11B02:G09 668 10374 Incyt14.E06.T3pINCY_377148 I:1513989:03B02:C03 669 10388 Incyt14.C18.T3pINCY_377338 I:1453450:03B02:B09 670 10463 Incyte6.P17.T3pINCY_353662 I:4592475:12A02:H09 671 10481 Incyte5.A17.T3pINCY_353072 I:1726307:10A02:A09 672 10508 Incyt14.L06.T3pINCY_377155 I:1900378:04B02:F03 673 10519 1655492 I:1655492:04A02:D09 674 10569 Incyte3.J08.T3pINCY_352169 I:2447969:08A01:E04 675 10594 1871362 I:1871362:05B01:A04 676 10601 1337615 I:1337615:05A01:E04 677 10650 Incyte3.J19.T3pINCY_352345 I:2456393:07B01:E10 678 10674 Incyte2.B19.T3pINCY_351953 I:1911622:06B01:A10 679 10684 4082816 I:4082816:06B01:F10 680 10686 Incyte2.N19.T3pINCY_351965 I:1450849:06B01:G10 681 10746 Incyt14.I19.T3pINCY_377360 I:1445895:03B01:E10 682 10762 Incyte8.J08.T3pINCY_354280 I:2852042:01B01:E04 683 10766 2071761 I:2071761:01B01:G04 684 10767 Incyt11.O08.T3pINCY_367920 I:1336836:01A01:H04 685 10777 2591814 I:2591814:01A01:E10 686 10801 Incyt10.B19.T3pINCY_367699 I:3951088:12A01:A10 687 10805 Incyt10.F19.T3pINCY_367703 I:3815547:12A01:C10 688 10815 Incyte6.O20.T3pINCY_353709 I:2881469:12A01:H10 689 10830 1438966 I:1438966:10B01:G04 690 10832 2174773 I:2174773:10B01:H04 691 10855 2555828 I:2555828:04A01:D04 692 10864 I1.P07.T3pINCY1_343616 I:2966620:04B01:H04 693 10870 I1.F19.T3pINCY1_343798 I:2832889:04B01:C10 694 10873 Incyt14.J19.T3pINCY_377361 I:1342493:04A01:E10 695 10921 1675571 I:1675571:08A02:E04 696 10924 1349433 I:1349433:08B02:F04 697 10925 1819282 I:1819282:08A02:G04 698 10936 1709017 I:1709017:08B02:D10 699 10937 3121962 I:3121962:08A02:E10 700 10938 3409027 I:3409027:08B02:E10 701 10941 1697490 I:1697490:08A02:G10 702 10961 Incyt15.A19.T3pINCY_377748 I:3176845:05A02:A10 703 10997 Incyte3.E20.T3pINCY_352356 I:3495906:07A02:C10 704 11035 1630804 I:1630804:06A02:F10 705 11050 Incyte6.I07.T3pINCY_353495 I:2494284:11B02:E04 706 11053 Incyte5.N08.T3pINCY_352941 I:3316536:11A02:G04 707 11057 Incyte5.B20.T3pINCY_353121 I:3743802:11A02:A10 708 11092 Incyt14.C20.T3pINCY_377370 I:1690653:03B02:B10 709 11100 Incyt14.K20.T3pINCY_377378 I:1636553:03B02:F10 710 11104 Incyt14.O20.T3pINCY_377382 I:1402228:03B02:H10 711 11112 Incyte8.H07.T3pINCY_354262 I:2918558:01B02:D04 712 11114 Incyt11.J08.T3pINCY_367915 I:2837773:01B02:E04 713 11149 Incyt10.N08.T3pINCY_367535 I:4049957:12A02:G04 714 11153 Incyt10.B20.T3pINCY_367715 I:2182353:12A02:A10 715 11201 2579602 I:2579602:04A02:A04 716 11202 2824181 I:2824181:04B02:A04 717 11208 2842835 I:2842835:04B02:D04 718 11221 1958560 I:1958560:04A02:C10 719 11223 I1.G20.T3pINCY1_343815 I:1749417:04A02:D10 720 11231 2495131 I:2495131:04A02:H10 721 11269 2133481 I:2133481:08A01:C05 722 11290 Incyte4.I21.T3pINCY_352760 I:1340424:08B01:E11 723 11322 1858171 I:1858171:05B01:E11 724 11335 Incyte3.G09.T3pINCY_352182 I:3360365:07A01:D05 725 11341 Incyte3.M09.T3pINCY_352188 I:1453445:07A01:G05 726 11347 Incyte3.C21.T3pINCY_352370 I:3334367:07A01:B11 727 11351 Incyte3.G21.T3pINCY_352374 I:3002566:07A01:D11 728 11380 1701809 I:1701809:06B01:B11 729 11396 Incyt10.C09.T3pINCY_367540 I:2796468:11B01:B05 730 11463 Incyt11.G10.T3pINCY_367944 I:1486087:01A01:D05 731 11473 lncyt11.A22.T3pINCY_368130 I:2555034:01A01:A11 732 11485 Incyt11.M22.T3pINCY_368142 I:1402967:01A01:G11 733 11489 Incyt10.B09.T3pINCY_367539 I:2884153:12A01:A05 734 11493 2608167 I:2608167:12A01:C05 735 11543 Incyte4.H22.T3pINCY_352775 I:2821541:10A01:D11 736 11568 I1.P09.T3pINCY1_343648 I:2883195:04B01:H05 737 11569 Incyt14.B21.T3pINCY_377385 I:1509602:04A01:A11 738 11583 Incyt14.P21.T3pINCY_377399 I:2832224:04A01:H11 739 11624 2343403 I:2343403:08B02:D05 740 11639 1880426 I:1880426:08A02:D11 741 11675 1511342 I:1511342:05A02:F11 742 11677 1805745 I:1805745:05A02:G11 743 11682 2707290 I:2707290:07B02:A05 744 11683 3872557 I:3872557:07A02:B05 745 11731 Incyte2.C22.T3pINCY_352002 I:1689068:06A02:B11 746 11736 3511355 I:3511355:06B02:D11 747 11739 Incyte2.K22.T3pINCY_352010 I:1699587:06A02:F11 748 11745 3097582 I:3097582:11A02:A05 749 11794 Incyt14.A22.T3pINCY_377400 I:2949427:03B02:A11 750 11806 Incyt14.M22.T3pINCY_377412 I:1525881:03B02:G11 751 11819 2158884 I:2158884:01A02:F05 752 11835 Incyt11.L21.T3pINCY_368125 I:2183580:01A02:F11 753 11836 Incyt11.L22.T3pINCY_368141 I:1806769:01B02:F11 754 11855 Incyt10.P10.T3pINCY_367569 I:3856893:12A02:H05 755 11928 Incyt14.H22.T3pINCY_377407 I:1683944:04B02:D11 756 11934 Incyt14.N22.T3pINCY_377413 I:1907952:04B02:G11 757 11945 Incyte7.I10.T3pINCY_353927 I:1817352:02A02:E05 758 11992 Incyte4.G23.T3pINCY_352790 I:1683245:08B01:D12 759 12025 3176179 I:3176179:05A01:E12 760 12035 Incyte3.C11.T3pINCY_352210 I:3175507:07A01:B06 761 12098 3553751 I:3553751:11B01:A06 762 12187 Incyt11.K24.T3pINCY_368172 I:1504554:01A01:F12 763 12201 Incyte6.I12.T3pINCY_353575 I:2957410:12A01:E06 764 12253 1725001 I:1725001:10A01:G12 765 12258 I1.B11.T3pINCY1_343666 I:2989991:04B01:A06 766 12259 Incyt14.D11.T3pINCY_377227 I:1514989:04A01:B06 767 12283 Incyt14.L23.T3pINCY_377427 I:1481225:04A01:F12 768 12295 Incyte7.G11.T3pINCY_353941 I:1624459:02A01:D06 769 12298 Incyte7.J11.T3pINCY_353944 I:2122820:02B01:E06 770 12329 2591352 I:2591352:08A02:E06 771 12332 2551421 I:2551421:08B02:F06 772 12369 Incyt15.A23.T3pINCY_377812 I:1252255:05A02:A12 773 12388 2674482 I:2674482:07B02:B06 774 12446 Incyte2.N24.T3pINCY_352045 I:1634046:06B02:G12 775 12499 Incyte9.C23.T3pINCY_354897 I:2513883:03A02:B12 776 12515 Incyt11.D11.T3pINCY_367957 I:2537805:01A02:B06 777 12540 Incyte8.L23.T3pINCY_354522 I:1730527:01B02:F12 778 12544 Incyt11.P24.T3pINCY_368177 I:1733522:01B02:H12 779 12546 3948420 I:3948420:12B01:A06 780 12548 3679736 I:3679736:12B01:B06 781 12555 Incyte6.L11.T3pINCY_353562 I:4083705:12A02:F06 782 16846 772853 I:772853:19A01:D07 783 16881 2028093 I:2028093:15A01:E07 784 16883 2132508 I:2132508:15A01:F07 785 16917 Incyte20.I02.Alpha2_380275 I:3144018:18B01:E01 786 16935 Incyte20.K14.Alpha2_380469 I:1967531:18B01:F07 787 16959 1426031 I:1426031:14B01:B07 788 17017 1001970 I:1001970:14A01:E07 789 17049 K1.I14.Laf3_324935 RG:160664:10006:E07 790 17090 341491 I:341491:13B01:A01 791 17119 2058935 I:2058935:13A01:H07 792 17122 AA858434 RG:1420946:10004:A01 793 17143 R51346 NIH50_39093 794 17236 Incyte4.C14.T3pINCY_352642 I:1602726:09B01:B07 795 17365 504786 I:504786:14A02:C07 796 17370 2103752 I:2103752:14B02:E07 797 17377 K1.B01.Laf3_324720 RG:197713:10007:A01 798 17379 K1.D01.Laf3_324722 RG:205212:10007:B01 799 17386 AI523571 RG:2117694:10016:E01 800 17395 K1.D13.Laf3_324914 RG:207395:10007:B07 801 17398 AI421409 RG:2097257:10016:C07 802 17422 Incyte18.N01.Alpha2_379490 I:349535:16B02:G01 803 17432 Incyte18.H13.Alpha2_379676 I:1965049:16B02:D07 804 17454 1995971 I:1995971:13B02:G01 805 17457 2132815 I:2132815:13A02:A07 806 17475 N44546 RG:272992:10008:B01 807 17479 W03193 RG:296383:10008:D01 808 17496 H08652 RG:45089:10005:D07 809 17511 K1.H02.Laf3_324742 RG:1409220:10013:D01 810 17524 K2.C13.Laf3_325298 RG:1705470:10015:B07 811 17603 1001730 I:1001730:15A01:B02 812 17609 1922531 I:1922531:15A01:E02 813 17618 707667 I:707667:15B01:A08 814 17726 1997233 I:1997233:14B01:G08 815 17730 AA128438 RG:526536:10002:A02 816 17746 AA070046 RG:530002:10002:A08 817 17756 AA197021 RG:608953:10002:F08 818 17793 2054420 I:2054420:13A01:A02 819 17795 1994472 I:1994472:13A01:B02 820 17851 H13036 NIH50_43563 821 17854 R18972 RG:33368:10004:G08 822 17867 AA281116 RG:711647:10010:F02 823 17878 K1.E15.Laf3_324947 RG:1047592:10012:C08 824 18006 Incyte21.F16.Alpha2_380880 I:2760114:19B02:C08 825 18062 2307314 I:2307314:14B02:G02 826 18069 1981145 I:1981145:14A02:C08 827 18097 R99405 RG:201268:10007:A08 828 18178 R20998 RG:36399:10005:A02 829 18187 W24158 RG:310019:10008:F02 830 18235 AA923101 RG:1521317:10013:F08 831 18305 743595 I:743595:15A01:A03 832 18311 2621547 I:2621547:15A01:D03 833 18314 1988412 I:1988412:15B01:E03 834 18316 1987738 I:1987738:15B01:F03 835 18321 1922944 I:1922944:15A01:A09 836 18323 1213932 I:1213932:15A01:B09 837 18362 2296027 I:2296027:19B01:E09 838 18431 1998269 I:1998269:14A01:H09 839 18445 R85309 RG:180296:10006:G03 840 18447 H30045 RG:190269:10006:H03 841 18454 AA131155 RG:587068:10002:C09 842 18460 AA167493 RG:609044:10002:F09 843 18464 AA197125 RG:629241:10002:H09 844 18471 Incyte21.G06.Alpha2_380721 I:1953051:16A01:D03 845 18473 Incyte21.I06.Alpha2_380723 I:518826:16A01:E03 846 18519 1997703 I:1997703:13A01:D09 847 18560 R14989 RG:35716:10004:H09 848 18571 K2.L05.Laf3_325179 RG:712070:10010:F03 849 18594 Incyte19.A06.Alpha2_379947 I:1997779:17B01:A03 850 18620 Incyte19.K18.Alpha2_380149 I:1998428:17B01:F09 851 18624 Incyte19.O18.Alpha2_380153 I:406788:17B01:H09 852 18665 1968413 I:1968413:15A02:E03 853 18683 552654 I:552654:15A02:F09 854 18687 637576 I:637576:15A02:H09 855 18693 Incyte20.F06.Alpha2_380336 I:606875:19A02:C03 856 18724 1962095 I:1962095:18B02:B03 857 18758 856900 I:856900:14B02:C03 858 18760 2132752 I:2132752:14B02:D03 859 18769 143987 I:143987:14A02:A09 860 18787 K1.D05.Laf3_324786 RG:206694:10007:B03 861 18797 N23769 RG:263708:10007:G03 862 18821 Incyte18.E05.Alpha2_379545 I:1461515:16A02:C03 863 18845 Incyte18.M17.Alpha2_379745 I:1425861:16A02:G09 864 18860 700559 I:700559:13B02:F03 865 18872 1844755 I:1844755:13B02:D09 866 18891 W30991 RG:310347:10008:F03 867 18894 H19237 RG:51009:10005:G03 868 18919 K1.H06.Laf3_324806 RG:1415437:10013:D03 869 18920 K2.G05.Laf3_325174 RG:1734353:10015:D03 870 18926 AI281021 RG:1872251:10015:G03 871 18937 K1.J18.Laf3_325000 RG:1476452:10013:E09 872 18942 K2.M17.Laf3_325372 RG:1895716:10015:G09 873 18988 Incyte4.L05.T3pINCY_352507 I:2069305:09B02:F03 874 19005 2674167 I:2674167:09A02:G09 875 19025 2296518 I:2296518:15A01:A10 876 19113 692827 I:692827:14A01:E04 877 19130 1998594 I:1998594:14B01:E10 878 19166 AA186459 RG:625691:10002:G10 879 19173 Incyte21.E08.Alpha2_380751 I:293495:16A01:C04 880 19183 3187911 I:3187911:16A01:H04 881 19219 406016 I:406016:13A01:B10 882 19227 671776 I:671776:13A01:F10 883 19259 H06516 NIH50_44180 884 19287 AA290719 RG:700320:10010:D10 885 19348 Incyte4.C20.T3pINCY_352738 I:2556708:09B01:B10 886 19370 136571 I:136571:15B02:E04 887 19376 Incyte18.O08.Alpha2_379603 I:1988674:15B02:H04 888 19389 556016 I:556016:15A02:G10 889 19401 483757 I:483757:19A02:E04 890 19444 1923893 I:1923893:18B02:B10 891 19473 130254 I:130254:14A02:A10 892 19482 2263936 I:2263936:14B02:E10 893 19506 AI335696 RG:1949583:10016:A10 894 19512 AI523861 RG:2116699:10016:D10 895 19517 K1.N19.Laf3_325020 RG:266649:10007:G10 896 19527 996772 I:996772:16A02:D04 897 19574 635178 I:635178:13B02:C10 898 19600 T83145 RG:110764:10005:H04 899 19636 K2.C19.Laf3_325394 RG:1706414:10015:B10 900 19641 K1.J20.Laf3_325032 RG:1476433:10013:E10 901 19667 Incyte19.C19.Alpha2_380157 I:1368834:17A02:B10 902 19684 Incyte4.D07.T3pINCY_352531 I:2680168:09B02:B04 903 19701 1515905 I:1515905:09A02:C10 904 19713 996104 I:996104:15A01:A05 905 19725 1966446 I:1966446:15A01:G05 906 19738 1999120 I:1999120:15B01:E11 907 19743 591358 I:591358:15A01:H11 908 19835 2055926 I:2055926:14A01:F11 909 19887 Incyte21.O10.Alpha2_380793 I:452536:16A01:H05 910 19907 2056035 I:2056035:13A01:B05 911 19922 2102320 I:2102320:13B01:A11 912 19946 R38438 RG:26394:10004:E05 913 19955 R42581 NIH50_31143 914 19996 AA745592 RG:1283072:10012:F11 915 20084 Incyte18.C22.Alpha2_379815 I:79576:15B02:B11 916 20170 1431632 I:1431632:14B02:E05 917 20171 234123 I:234123:14A02:F05 918 20184 2027012 I:2027012:14B02:D11 919 20185 128997 I:128997:14A02:E11 920 20209 K1.B21.Laf3_325040 RG:204966:10007:A11 921 20212 AI377014 RG:2065950:10016:B11 922 20262 1995380 I:1995380:13B02:C05 923 20302 H19394 RG:51505:10005:G05 924 20331 K1.L10.Laf3_324874 RG:1519327:10013:F05 925 20401 1824332 I:1824332:09A02:A11 926 20422 735149 I:735149:15B01:C06 927 20436 1530218 I:1530218:15B01:B12 928 20508 1963854 I:1963854:18B01:F12 929 20530 167371 I:167371:14B01:A12 930 20551 K1.G12.Laf3_324901 RG:151093:10006:D06 931 20554 AA143470 RG:591811:10002:E06 932 20557 R87294 RG:180978:10006:G06 933 20558 AA187806 RG:624431:10002:G06 934 20570 AA159912 RG:593090:10002:E12 935 20587 Incyte21.K12.Alpha2_380821 I:2303180:16A01:F06 936 20617 911015 I:911015:13A01:E06 937 20624 1968576 I:1968576:13B01:H06 938 20676 K1.C11.Laf3_324881 RG:967302:10012:B06 939 20696 AA627319 RG:1157566:10012:D12 940 20714 Incyte19.I12.Alpha2_380051 I:1943853:17B01:E06 941 20716 1218621 I:1218621:17B01:F06 942 20799 1967095 I:1967095:15A02:H12 943 20878 998612 I:998612:14B02:G06 944 20892 699410 I:699410:14B02:F12 945 20937 Incyte18.I11.Alpha2_379645 I:429577:16A02:E06 946 20939 Incyte18.K11.Alpha2_379647 I:2117221:16A02:F06 947 20976 1782172 I:1782172:13B02:H06 948 20986 1986809 I:1986809:13B02:E12 949 20990 1986550 I:1986550:13B02:G12 950 20999 W07144 RG:300017:10008:D06 951 21029 AA890655 RG:1405692:10013:C06 952 21035 K1.L12.Laf3_324906 RG:1519656:10013:F06 953 21038 AI268327 RG:1880845:10015:G06 954 21050 K2.I23.Laf3_325464 RG:1841029:10015:E12 955 21189 RTA22200010F.e.10.1.P M00056386D:H12 956 21212 1.L13.Beta5_309680 M00056193B:C11 957 21214 1.N13.Beta5_309682 M00056193B:D06 958 21234 4.B13.Beta5_310822 M00054882C:C06 959 21245 4.M13.Beta5_310833 M00054680B:D06 960 21290 RTA00002690F.a.18.2.P M00042437B:G03 961 21307 RTA22200001F.g.08.1.P M00042702D:B02 962 21339 RTA22200011F.f.10.1.P M00056569A:B12 963 21345 W79308 RG:346944:10009:A01 964 21349 K2.E02.Laf3_325124 RG:376801:10009:C01 965 21391 RTA22200016F.o.05.1.P M00057273B:H10 966 21407 RTA22200017F.e.08.1.P M00057336A:C12 967 21539 1.C02.Beta5_309495 M00055932A:C02 968 21543 1.G02.Beta5_309499 M00055935D:B06 969 21546 2.J01.Beta5_309870 M00056908D:D08 970 21568 2.P13.Beta5_310068 M00056952B:C08 971 21569 4.A02.Beta5_310645 M00054728C:E03 972 21575 4.G02.Beta5_310651 M00054730D:F06 973 21650 RTA22200009F.o.15.1.P M00042867B:F03 974 21654 RTA22200009F.o.18.1.P M00042868A:A06 975 21658 RTA22200009F.p.01.1.P M00042869D:B09 976 21660 RTA22200009F.p.01.1.P M00042869D:B09 977 21671 2.G01.Beta5_309867 M00056719C:G03 978 21693 2.M13.Beta5_310065 M00056785D:G01 979 21694 AI251081 RG:2007272:20003:G07 980 21701 AI066797 RG:1637588:10014:C01 981 21705 AI123832 RG:1651303:10014:E01 982 21735 3.G01.Beta5_310251 M00043310D:E11 983 21766 RTA22200025F.o.18.2.P M00055398B:C07 984 21781 RTA22200012F.a.23.1.P M00056667C:H09 985 21786 RTA22200026F.d.20.1.P M00055423C:C03 986 21791 3.P14.Beta5_310468 M00056669B:E07 987 21947 4.K15.Beta5_310863 M00054684B:C07 988 21966 5.N03.Beta5_311058 M00057194B:G12 989 22003 RTA22200001F.g.22.1.P M00042711B:G09 990 22040 ovarian1.G15.amp3_326923 RG:1862072:20001:D08 991 22071 W87399 RG:417093:10009:D08 992 22078 K2.N16.Laf3_325357 RG:809602:10011:G08 993 22132 RTA22200022F.n.06.1.P M00054980D:H02 994 22227 AI252058 RG:1983965:20002:B08 995 22279 4.G04.Beta5_310683 M00054737D:F10 996 22291 4.C16.Beta5_310871 M00054785D:G05 997 22299 4.K16.Beta5_310879 M00054806B:G03 998 22352 RTA22200009F.l.07.2.P M00042842B:E02 999 22414 AA595123 RG:1102368:10003:G02 1000 22423 AI040910 RG:1647954:10014:D08 1001 22451 RTA00002691F.d.11.3.P M00043372B:B06 1002 22597 RTA22200010F.h.09.1.P M00056417A:F02 1003 22604 1.L05.Beta5_309552 M00056150C:A10 1004 22608 1.P05.Beta5_309556 M00056151C:A12 1005 22627 RTA22200020F.j.04.1.P M00054645B:C12 1006 22629 4.E05.Beta5_310697 M00054646A:B10 1007 22632 4.H05.Beta5_310700 M00054858D:F04 1008 22633 RTA22200020F.j.09.1.P M00054647A:A09 1009 22637 RTA22200020F.j.11.1.P M00054647D:E01 1010 22678 5.F17.Beta5_311274 M00057231A:G04 1011 22697 RTA22200001F.c.18.1.P M00042551B:D12 1012 22698 RTA22200009F.c.12.2.P M00042513A:D03 1013 22703 RTA22200001F.c.21.1.P M00042551D:D12 1014 22710 RTA22200009F.h.06.1.P M00042803C:F11 1015 22714 RTA22200009F.h.11.1.P M00042805D:D12 1016 22715 RTA22200001F.i.13.1.P M00042731A:G04 1017 22729 RTA22200011F.b.21.1.P M00056537D:B06 1018 22775 K2.G18.Laf3_325382 RG:417109:10009:D09 1019 22848 RTA22200022F.o.15.1.P M00054995B:F02 1020 22896 RTA22200007F.b.23.1.P M00056151C:A12 1021 22931 ovarian1.C18.amp3_326967 RG:1983997:20002:B09 1022 22979 4.C06.Beta5_310711 M00054744C:B02 1023 23050 RTA22200009F.l.19.2.P M00042845D:A12 1024 23053 RTA22200001F.o.20.1.P M00054800C:H10 1025 23097 2.I17.Beta5_310125 M00056809B:A12 1026 23118 AA595100 RG:1102907:10003:G03 1027 23120 AA640934 RG:1173536:10003:H03 1028 23127 AI027379 RG:1650120:10014:D09 1029 23143 RTA22200018F.j.04.1.P M00043329D:E09 1030 23153 RTA22200018F.p.12.1.P M00043376A:G08 1031 23193 RTA22200012F.c.07.1.P M00056683B:F08 1032 23351 4.G19.Beta5_310923 M00054700C:E02 1033 23407 1562.P22.gz43_208154 M00042570C:H05 1034 23416 RTA22200009F.i.02.2.P M00042811B:A05 1035 23511 2.H20.Beta5_310172 M00042457C:A05 1036 23513 2.J20.Beta5_310174 M00042457C:A05 1037 23514 RTA22200019F.k.01.1.P M00054520A:D04 1038 23542 RTA22200022F.p.04.1.P M00055001A:B01 1039 23544 RTA22200022F.p.07.1.P M00055002B:G06 1040 23637 AI251722 RG:1984571:20002:C10 1041 23678 2.N19.Beta5_310162 M00056964D:C08 1042 23689 4.I08.Beta5_310749 M00054752A:E11 1043 23695 4.O08.Beta5_310755 M00054760D:B10 1044 23743 RTA22200016F.a.11.1.P M00057156D:C12 1045 23755 RTA22200001F.p.18.1.P M00054917B:G02 1046 23758 RTA22200009F.m.16.1.P M00042850D:A06 1047 23765 RTA22200002F.f.19.1.P M00055468D:D05 1048 23770 RTA22200010F.b.10.1.P M00056360A:D09 1049 23772 RTA22200010F.b.11.1.P M00056360A:E07 1050 23776 RTA22200010F.b.17.1.P M00056362D:E05 1051 23784 AI305307 RG:1997021:20003:D04 1052 23798 AI305997 RG:1996788:20003:C10 1053 23813 AI017336 RG:1638979:10014:C04 1054 23816 AA600197 RG:949960:10003:D04 1055 23831 AI027534 RG:1650444:10014:D10 1056 23847 3.G07.Beta5_310347 M00043350A:C04 1057 23875 3.D08.Beta5_310360 M00056646D:G05 1058 23889 RTA22200012F.c.19.1.P M00056688C:E07 1059 24014 1.N09.Beta5_309618 M00056175D:B05 1060 24033 4.A09.Beta5_310757 M00054654A:F12 1061 24034 4.B09.Beta5_310758 M00054868D:F12 1062 24064 4.P21.Beta5_310964 M00054922B:B04 1063 24074 5.J09.Beta5_311150 M00057211D:A03 1064 24094 5.N21.Beta5_311346 M00057253A:C02 1065 24099 RTA22200001F.e.17.1.P M00042573B:A02 1066 24115 RTA22200001F.k.19.1.P M00042885C:A12 1067 24119 RTA22200001F.k.23.1.P M00042886D:H10 1068 24126 RTA22200009F.i.21.2.P M00042818D:A08 1069 24128 RTA22200009F.i.22.2.P M00042819A:C07 1070 24137 RTA22200011F.d.18.1.P M00056553C:E10 1071 24193 2.B10.Beta5_310006 M00057302A:F08 1072 24209 2.B22.Beta5_310198 M00042460B:A08 1073 24213 2.F22.Beta5_310202 M00042516B:A08 1074 24222 3.M22.Beta5_310593 M00054529C:G04 1075 24246 RTA22200023F.a.09.1.P M00055015C:H02 1076 24289 6.A10.Beta5_311541 M00055204B:C04 1077 24315 6.K22.Beta5_311743 M00055254C:E11 1078 24395 4.K10.Beta5_310783 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521.H08.laf3_559480 RG:144155:Order7TM17:D04 1871 32304 R53113 RG:154422:Order7TM18:A10 1872 32309 521.F20.laf3_559670 RG:143670:Order7TM17:C10 1873 32317 R49761 RG:152624:Order7TM17:G10 1874 32320 522.A08.laf3_559857 RG:365486:Order7TM25:A04 1875 32347 AA292684 RG:713779:Order7TM30:F10 1876 32358 AA460529 RG:796624:Order7TM32:D04 1877 32371 AA761894 RG:1290472:Order7TM34:B10 1878 32386 524.C08.laf3_560627 RG:1387448:Order7TM36:B04 1879 32388 AA844385 RG:1390752:Order7TM36:C04 1880 32395 AA913293 RG:1554722:Order7TM38:F04 1881 32465 AI254029 RG:1983593:20002:A10 1882 32469 AI251722 RG:1984571:20002:C10 1883 32480 1TNT051800.A05.GZ43_421369 1TNT051800A05 1884 32484 1TNT051800.C05.GZ43_421371 1TNT051800C05 1885 32488 538.E05.BETA5_582883 1TNT051800E05 1886 32499 5383.B11.T3_583120 3TNT052200B11 1887 32506 538.F11.BETA5_582932 1TNT051800F11 1888 32512 539.A09.Laf3_581123 RG:2124082:8119907:A05 1889 32516 539.E09.laf3_581127 RG:2160113:8119907:C05 1890 32544 T81096 RG:109165:12039905:A05 1891 32556 N30787 RG:257079:12039905:G05 1892 32558 518.O09.laf3_548219 RG:300634:12039905:H05 1893 32564 R55625 RG:154770:12039905:C11 1894 32574 518.O21.laf3_548411 RG:325930:12039905:H11 1895 32580 519.E09.laf3_548593 RG:179266:Order7TM19:C05 1896 32583 519.H09.laf3_548596 RG:263993:Order7TM21:D05 1897 32591 519.P09.laf3_548604 RG:273969:Order7TM21:H05 1898 32594 519.C21.laf3_548783 RG:178479:Order7TM19:B11 1899 32596 H51124 RG:179642:Order7TM19:C11 1900 32628 520.E21.laf3_559301 RG:321260:Order7TM23:C11 1901 32645 T77432 RG:113840:Order7TM16:C05 1902 32652 521.M09.laf3_559501 RG:48922:Order7TM02:G05 1903 32654 521.O09.laf3_559503 RG:50127:Order7TM02:H05 1904 32662 521.G21.laf3_559687 RG:44286:Order7TM02:D11 1905 32666 521.K21.laf3_559691 RG:48256:Order7TM02:F11 1906 32670 521.O21.laf3_559695 RG:51009:Order7TM02:H11 1907 32684 AA702455 RG:447950:Order7TM26:G05 1908 32688 522.A21.laf3_560065 RG:415681:Order7TM26:A11 1909 32702 AA779154 RG:452641:Order7TM26:H11 1910 32725 AA650031 RG:1187678:Order7TM33:C11 1911 32733 AA743401 RG:1272563:Order7TM33:G11 1912 32751 524.P09.laf3_560656 RG:1752807:Order7TM39:H05 1913 32775 AI638529 RG:2240207:Order7TM41:D05 1914 32799 525.P21.laf3_561232 RG:2342176:Order7TM41:H11 1915 32811 AI223784 RG:2003087:20003:F05 1916 32828 AA250856 RG:684365:OrderP01:G11 1917 32829 AI246847 RG:2007337:20003:G11 1918 32830 526.O21.laf3_561615 RG:753277:OrderP01:H11 1919 32835 4ATNT052400.A03.T3_421661 4ATNT052400A03 1920 32839 PL4B052400.E01.GZ43_421685 PL4B052400E01 1921 32842 5382.F05.BETA5_582980 2TNT052200F05 1922 32843 PL4B052400.E04.GZ43_421709 PL4B052400E04 1923 32848 5382.A11.BETA5_583023 2TNT052200A11 1924 32854 5382.D11.BETA5_583026 2TNT052200D11 1925 32872 AI150354 RG:1752018:OrderK02:E05 1926 32883 539.D22.Laf3_581334 RG:180447:OrderK01:B11 1927 32891 539.L22.Laf3_581342 RG:470447:OrderK01:F11 1928 32904 AI033477 RG:1655516:12039906:E05 1929 32907 AA834081 RG:1422219:Order7TM11:F05 1930 32930 519.C10.laf3_548607 RG:201469:Order7TM20:B05 1931 32932 519.E10.laf3_548609 RG:205963:Order7TM20:C05 1932 32934 519.G10.laf3_548611 RG:211565:Order7TM20:D05 1933 32938 519.K10.laf3_548615 RG:232881:Order7TM20:F05 1934 32940 519.M10.laf3_548617 RG:236186:Order7TM20:G05 1935 32952 519.I22.laf3_548805 RG:229279:Order7TM20:E11 1936 32963 520.D10.laf3_559124 RG:23984:Order7TM01:B05 1937 32998 521.G10.laf3_559511 RG:158151:Order7TM18:D05 1938 33016 521.I22.laf3_559705 RG:163004:Order7TM18:E11 1939 33018 521.K22.laf3_559707 RG:165830:Order7TM18:F11 1940 33023 521.P22.laf3_559712 RG:153398:Order7TM17:H11 1941 33037 522.N10.laf3_559902 RG:714057:Order7TM30:G05 1942 33044 522.E22.laf3_560085 RG:378869:Order7TM25:C11 1943 33047 522.H22.laf3_560088 RG:712463:Order7TM30:D11 1944 33109 AA919075 RG:1535701:Order7TM38:C11 1945 33122 AI263529 RG:1857034:Order7TM40:B05 1946 33125 525.F10.laf3_561046 RG:2365503:Order7TM42:C05 1947 33135 525.P10.laf3_561056 RG:2504825:Order7TM42:H05 1948 33136 AI248597 RG:1850163:Order7TM40:A11 1949 33147 AI820024 RG:2408918:Order7TM42:F11 1950 33148 AI553937 RG:2090491:Order7TM40:G11 1951 33155 AI251395 RG:1983835:20002:B05 1952 33180 526.M22.laf3_561629 RG:2271099:OrderP02:G11 1953 33191 5383.D06.T3_583082 3TNT052200D06 1954 33202 538.B12.BETA5_582936 1TNT051800B12 1955 33204 538.C12.BETA5_582937 1TNT051800C12 1956 33209 5383.E12.T3_583131 3TNT052200E12 1957 33216 539.A11.Laf3_581155 RG:2124966:8119907:A06 1958 33218 AI457674 RG:2144771:8119907:B06 1959 33220 AI478225 RG:2161567:8119907:C06 1960 33221 539.F11.Laf3_581160 RG:1322461:12039907:C06 1961 33222 539.G11.Laf3_581161 RG:2213638:8119907:D06 1962 33232 539.A23.Laf3_581347 RG:2131578:8119907:A12 1963 33235 AA662728 RG:1218062:12039907:B12 1964 33244 539.M23.Laf3_581359 RG:2341674:8119907:G12 1965 33248 518.A11.laf3_548237 RG:110380:12039905:A06 1966 33249 518.B11.laf3_548238 RG:1412814:12039908:A06 1967 33253 518.F11.laf3_548242 RG:1526787:12039908:C06 1968 33254 518.G11.laf3_548243 RG:183599:12039905:D06 1969 33261 AI346645 RG:1926602:12039908:G06 1970 33275 518.L23.laf3_548440 RG:1872818:12039908:F12 1971 33287 N28612 RG:264033:Order7TM21:D06 1972 33291 519.L11.laf3_548632 RG:269093:Order7TM21:F06 1973 33293 519.N11.laf3_548634 RG:271623:Order7TM21:G06 1974 33294 H38515 RG:192671:Order7TM19:H06 1975 33301 519.F23.laf3_548818 RG:262317:Order7TM21:C12 1976 33328 520.A23.laf3_559329 RG:308004:Order7TM23:A12 1977 33330 520.C23.laf3_559331 RG:309559:Order7TM23:B12 1978 33350 R61591 RG:37697:Order7TM02:D06 1979 33351 T91350 RG:116459:Order7TM16:D06 1980 33355 521.L11.laf3_559532 RG:126266:Order7TM16:F06 1981 33359 521.P11.laf3_559536 RG:134800:Order7TM16:H06 1982 33360 521.A23.laf3_559713 RG:39932:Order7TM02:A12 1983 33374 521.O23.laf3_559727 RG:51276:Order7TM02:H12 1984 33396 AA678187 RG:430831:Order7TM26:C12 1985 33417 AA731087 RG:1251730:Order7TM33:E06 1986 33434 523.K23.laf3_560491 RG:728661:Order7TM31:F12 1987 33458 AA810410 RG:1338465:Order7TM35:B12 1988 33486 AA902928 RG:1516750:Order7TM37:H06 1989 33496 AA909778 RG:1476569:Order7TM37:E12 1990 33506 526.C11.laf3_561443 RG:151456:OrderP01:B06 1991 33513 AI223471 RG:2002542:20003:E06 1992 33531 AI265824 RG:2006592:20003:F12 1993 33533 AI246860 RG:2007366:20003:G12 1994 33539 5384.B06.T3_583176 4ATNT052400B03 1995 33551 PL4B052400.F07.GZ43_421734 PL4B052400F07 1996 33554 5382.B12.BETA5_583032 2TNT052200B12 1997 33555 5384.B12.T3_583224 4ATNT052400H03 1998 33561 PL4B052400.H03.GZ43_421704 PL4B052400H03 1999 33563 PL4B052400.D05.GZ43_421716 PL4B052400D05 2000 33565 PL4B052400.H06.GZ43_421728 PL4B052400H06 2001 33593 539.J24.Laf3_581372 RG:362359:OrderK01:E12 2002 33603 518.D12.laf3_548256 RG:1173873:Order7TM11:B06 2003 33607 AA837505 RG:1410138:Order7TM11:D06 2004 33615 518.P12.laf3_548268 RG:1592447:Order7TM11:H06 2005 33618 AA702766 RG:447683:12039906:B12 2006 33621 518.F24.laf3_548450 RG:1239284:Order7TM11:C12 2007 33623 AA838525 RG:1418951:Order7TM11:D12 2008 33629 518.N24.laf3_548458 RG:1486533:Order7TM11:G12 2009 33634 519.C12.laf3_548639 RG:201628:Order7TM20:B06 2010 33636 R98050 RG:206795:Order7TM20:C06 2011 33664 520.A12.laf3_559153 RG:343572:Order7TM24:A06 2012 33672 W95805 RG:358318:Order7TM24:E06 2013 33680 520.A24.laf3_559345 RG:344338:Order7TM24:A12 2014 33682 520.C24.laf3_559347 RG:345553:Order7TM24:B12 2015 33690 AA016156 RG:360639:Order7TM24:F12 2016 33693 R34661 RG:36928:Order7TM01:G12 2017 33703 521.H12.laf3_559544 RG:144675:Order7TM17:D06 2018 33704 H22158 RG:160545:Order7TM18:E06 2019 33716 R73930 RG:156777:Order7TM18:C12 2020 33727 R48093 RG:153417:Order7TM17:H12 2021 33729 AA278452 RG:703940:Order7TM30:A06 2022 33740 AA701039 RG:397599:Order7TM25:G06 2023 33742 522.O12.laf3_559935 RG:399390:Order7TM25:H06 2024 33748 AA778077 RG:379708:Order7TM25:C12 2025 33755 522.L24.laf3_560124 RG:713954:Order7TM30:F12 2026 33800 AA843787 RG:1405420:Order7TM36:E06 2027 33802 524.K12.laf3_560699 RG:1409375:Order7TM36:F06 2028 33819 524.L24.laf3_560892 RG:1559941:Order7TM38:F12 2029 33823 524.P24.laf3_560896 RG:1571250:Order7TM38:H12 2030 33842 AI264420 RG:1872799:Order7TM40:B12 2031 33851 525.L24.laf3_561276 RG:2408975:Order7TM42:F12 2032 33892 529.D01.beta5_565388 M00074843D:D02 2033 33902 529.N01.beta5_565398 M00074844D:F09 2034 33919 529.O13.beta5_565591 M00073985B:C09 2035 33923 527.C01.beta5_564619 M00073796C:C06 2036 33925 2540.F24.GZ43_372151 M00073796D:B08 2037 33930 527.J01.beta5_564626 M00072996B:A10 2038 33938 527.B13.beta5_564810 M00074343B:B03 2039 33940 2472.E21.GZ43_360966 M00074343B:B09 2040 33950 2472.G02.GZ43_360995 M00074346D:A10 2041 33951 527.O13.beta5_564823 M00073812A:E09 2042 33965 536.N02.beta5_568934 M00073442B:D12 2043 33973 536.F14.beta5_569118 M00073469B:A09 2044 33979 2367.I16.GZ43_346202 M00073469D:C06 2045 33983 536.P14.beta5_569128 M00073469D:H04 2046 34000 535.P01.beta5_568536 M00073824A:C04 2047 34002 535.B13.beta5_568714 M00073839A:D05 2048 34003 535.C13.beta5_568715 M00075619B:A04 2049 34005 2499.F08.GZ43_365363 M00075621A:F06 2050 34012 535.L13.beta5_568724 M00073843A:C10 2051 34033 532.A13.beta5_566793 M00075166A:A12 2052 34034 532.B13.beta5_566794 M00074666D:B04 2053 34041 2491.A18.GZ43_363614 M00075167A:E12 2054 34058 2472.N19.GZ43_361180 M00074374D:A08 2055 34062 531.N01.beta5_566230 M00074377C:G04 2056 34066 531.B13.beta5_566410 M00074402C:C03 2057 34072 531.H13.beta5_566416 M00074423A:B06 2058 34075 2474.J01.GZ43_361834 M00074481A:G09 2059 34120 534.H01.beta5_567760 M00073715A:F05 2060 34124 534.L01.beta5_567764 M00073715B:B06 2061 34131 534.C13.beta5_567947 M00073885B:E06 2062 34134 534.F13.beta5_567950 M00073738C:F01 2063 34139 534.K13.beta5_567955 M00073885D:G11 2064 34142 534.N13.beta5_567958 M00073741A:G07 2065 34167 530.G13.beta5_565967 M00073001A:F07 2066 34168 530.H13.beta5_565968 M00074235A:F11 2067 34184 2506.D23.GZ43_366652 M00073853B:C04 2068 34188 2506.E17.GZ43_366670 M00073854B:G11 2069 34195 2467.D11.GZ43_360548 M00074962C:C08 2070 34202 533.J13.beta5_567186 M00073863C:F12 2071 34203 2467.D20.GZ43_360557 M00074966D:E08 2072 34228 537.D13.beta5_569868 M00074277C:C10 2073 34238 2459.C06.GZ43_357046 M00074278B:F02 2074 34252 2561.C08.GZ43_376287 M00074111A:E09 2075 34260 529.D14.beta5_565596 M00074135D:E06 2076 34270 529.N14.beta5_565606 M00074138D:A08 2077 34271 529.O14.beta5_565607 M00074019C:H06 2078 34272 529.P14.beta5_565608 M00074138D:E07 2079 34274 2560.C15.GZ43_375142 M00074079A:E07 2080 34278 527.F02.beta5_564638 M00074079C:H03 2081 34283 527.K02.beta5_564643 M00074198C:A10 2082 34287 527.O02.beta5_564647 M00074198D:D10 2083 34289 527.A14.beta5_564825 M00074208B:G09 2084 34290 527.B14.beta5_564826 M00074091D:F06 2085 34294 527.F14.beta5_564830 M00074093B:G07 2086 34300 527.L14.beta5_564836 M00074094B:F10 2087 34302 527.N14.beta5_564838 M00074095C:E06 2088 34310 536.E01.beta5_568909 M00074159A:C10 2089 34322 536.A13.beta5_569097 M00074175D:D08 2090 34330 536.I13.beta5_569105 M00074177A:G11 2091 34345 2475.O20.GZ43_362357 M00074567C:E04 2092 34359 535.G14.beta5_568735 M00074602A:F03 2093 34365 535.M14.beta5_568741 M00074604C:G09 2094 34366 535.N14.beta5_568742 M00073517C:B05 2095 34370 532.B02.beta5_566618 M00073897B:D12 2096 34375 532.G02.beta5_566623 M00074872B:A12 2097 34376 2542.N11.GZ43_373098 M00073898B:B05 2098 34392 2555.D22.GZ43_373253 M00073916A:B07 2099 34402 531.B02.beta5_566234 M00074296B:B03 2100 34412 531.L02.beta5_566244 M00074298B:E09 2101 34432 531.P14.beta5_566440 M00074320C:A06 2102 34498 2562.P24.GZ43_375847 M00075409D:H01 2103 34514 530.B14.beta5_565978 M00075412A:G03 2104 34518 530.F14.beta5_565982 M00075431D:F08 2105 34542 2491.K18.GZ43_363854 M00075216B:A03 2106 34544 2491.K21.GZ43_363857 M00075217A:B04 2107 34548 2496.B16.GZ43_364123 M00075241A:F08 2108 34560 2496.D03.GZ43_364158 M00075245A:A06 2109 34563 537.C02.beta5_569691 M00074909B:C10 2110 34565 537.E02.beta5_569693 M00074909D:F05 2111 34569 537.I02.beta5_569697 M00074910B:C09 2112 34574 537.N02.beta5_569702 M00074738C:G02 2113 34575 2465.P03.GZ43_358427 M00074911B:F05 2114 34588 2483.G10.GZ43_359809 M00074757A:F04 2115 34607 529.O03.beta5_565431 M00073969A:A02 2116 34610 529.B15.beta5_565610 M00074857C:F04 2117 34615 529.G15.beta5_565615 M00073986C:B02 2118 34616 529.H15.beta5_565616 M00074858C:E07 2119 34659 2367.D02.GZ43_346068 M00073445C:C02 2120 34661 2367.D05.GZ43_346071 M00073445D:H03 2121 34671 536.P04.beta5_568968 M00073447D:F01 2122 34683 536.L16.beta5_569156 M00073471C:F03 2123 34691 535.C03.beta5_568555 M00075560B:E01 2124 34713 2499.G09.GZ43_365388 M00075626A:F03 2125 34714 535.J15.beta5_568754 M00073844D:F01 2126 34719 535.O15.beta5_568759 M00075626D:H03 2127 34729 2490.I24.GZ43_363428 M00075088A:H02 2128 34734 2481.E13.GZ43_358996 M00074641D:A12 2129 34741 532.E15.beta5_566829 M00075172D:H03 2130 34766 531.N03.beta5_566262 M00074409D:A04 2131 34783 531.O15.beta5_566455 M00074493C:D09 2132 34784 2473.J12.GZ43_361461 M00074413A:G11 2133 34818 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527.A23.beta5_564969 M00073819A:A12 2428 37467 527.K23.beta5_564979 M00073819C:F05 2429 37469 527.M23.beta5_564981 M00073819D:A05 2430 37479 2367.H19.GZ43_346181 M00073468A:G03 2431 37510 2541.L10.GZ43_372665 M00073838C:F02 2432 37522 2506.C08.GZ43_366613 M00073850A:H09 2433 37528 2506.C14.GZ43_366619 M00073850D:A03 2434 37532 535.L23.beta5_568884 M00073851A:C04 2435 37551 532.O11.beta5_566775 M00075165D:B06 2436 37561 2491.I06.GZ43_363794 M00075203A:G06 2437 37575 531.G11.beta5_566383 M00074473B:A09 2438 37579 531.K11.beta5_566387 M00074474D:F08 2439 37581 531.M11.beta5_566389 M00074476A:A06 2440 37584 531.P11.beta5_566392 M00074441B:A02 2441 37591 2474.P14.GZ43_361991 M00074514A:E08 2442 37592 531.H23.beta5_566576 M00074425C:E05 2443 37595 531.K23.beta5_566579 M00074515A:E02 2444 37597 531.M23.beta5_566581 M00074515A:G08 2445 37637 534.E11.beta5_567917 M00073884A:D12 2446 37638 534.F11.beta5_567918 M00073735C:E04 2447 37660 534.L23.beta5_568116 M00073757A:G10 2448 37662 534.N23.beta5_568118 M00073757C:B09 2449 37667 2505.A09.GZ43_366182 M00072979C:F02 2450 37677 530.M11.beta5_565941 M00072980B:C06 2451 37680 2458.C03.GZ43_356659 M00074234B:B05 2452 37682 2458.L01.GZ43_356873 M00074256D:D03 2453 37688 2458.L05.GZ43_356877 M00074258A:G05 2454 37692 530.L23.beta5_566132 M00074258B:F07 2455 37702 2506.I05.GZ43_366754 M00073861B:C11 2456 37707 533.K11.beta5_567155 M00074960C:H09 2457 37715 2467.J18.GZ43_360699 M00072983C:F04 2458 37724 533.L23.beta5_567348 M00073870A:E04 2459 37729 537.A11.beta5_569833 M00073595D:H05 2460 37731 2535.N11.GZ43_370410 M00073596B:B12 2461 37734 2459.A22.GZ43_357014 M00074274D:F10 2462 37735 537.G11.beta5_569839 M00073597A:A03 2463 37743 2535.O02.GZ43_370425 M00073597D:H01 2464 37748 537.D23.beta5_570028 M00074293D:H07 2465 37760 537.P23.beta5_570040 M00074296B:B11 2466 37764 529.D12.beta5_565564 M00074134A:E08 2467 37768 2561.K01.GZ43_376472 M00074135A:F02 2468 37794 527.B12.beta5_564794 M00074089D:E03 2469 37805 527.M12.beta5_564805 M00074208B:F09 2470 37826 2456.H06.GZ43_356002 M00074174B:H08 2471 37827 2475.H07.GZ43_362176 M00074540C:E02 2472 37831 536.H11.beta5_569072 M00074541C:E08 2473 37834 536.I11.beta5_569073 M00074175A:D08 2474 37859 535.C12.beta5_568699 M00074594B:A07 2475 37861 535.E12.beta5_568701 M00074594B:E10 2476 37865 2480.I08.GZ43_358703 M00074596D:B12 2477 37868 535.L12.beta5_568708 M00073514A:G01 2478 37874 2368.H23.GZ43_346569 M00073532C:H12 2479 37877 2481.B11.GZ43_358922 M00074633B:H01 2480 37882 535.J24.beta5_568898 M00073537D:C03 2481 37887 2481.C09.GZ43_358944 M00074635B:C07 2482 37895 2465.H15.GZ43_358247 M00074890B:C01 2483 37897 2465.H17.GZ43_358249 M00074890B:D05 2484 37914 532.J24.beta5_566978 M00073925B:A01 2485 37926 531.F12.beta5_566398 M00074315C:F09 2486 37929 531.I12.beta5_566401 M00074713B:F02 2487 37947 531.K24.beta5_566595 M00074735C:A11 2488 37951 531.O24.beta5_566599 M00074735D:G06 2489 38020 2498.M13.GZ43_365152 M00075444D:F05 2490 38022 2498.M15.GZ43_365154 M00075448D:A02 2491 38026 530.J12.beta5_565954 M00075414D:G01 2492 38029 2565.N09.GZ43_398087 M00073773D:B10 2493 38048 530.P24.beta5_566152 M00075474C:G02 2494 38050 2496.A04.GZ43_364087 M00075235C:E03 2495 38068 533.D24.beta5_567356 M00075283A:F04 2496 38074 533.J24.beta5_567362 M00075285D:A02 2497 38083 2466.C04.GZ43_360133 M00074918B:F03 2498 38089 2466.C16.GZ43_360145 M00074919C:D12 2499 38091 2466.C22.GZ43_360151 M00074919D:H09 2500 38096 537.P12.beta5_569864 M00074754C:G02 2501 38101 537.E24.beta5_570045 M00074935A:D06 2502 38103 537.G24.beta5_570047 M00074935B:C06 2503 38107 537.K24.beta5_570051 M00074935C:E08 2504 38110 537.N24.beta5_570054 M00074782B:F01 2505 38112 537.P24.beta5_570056 M00074783B:B11

Table 15 (on a CD ROM filed herewith) provides the results for gene products expressed by at least 2-fold or greater in the prostate tumor samples relative to normal tissue samples in at least 20% of the patients tested. Table 15 includes: 1) the spot identification number (“Spot ID”); 2) the GenBank Accession Number of the publicly available sequence corresponding to the polynucleotide (“GenBankHit”); 3) a description of the GenBank sequence (“GenBankDesc”); 4) the score of the similarity of the polynucleotide sequence and the GenBank sequence (“GenBankScore”); 5) the number of patients analyzed; 6) the percentage of patients tested in which expression levels (e.g., as message level) of the gene was at least 2-fold greater in cancerous tissue than in matched normal tissue (“>=2×”); 7) the percentage of patients tested in which expression levels (e.g., as message level) of the gene was at least 5-fold greater in cancerous tissue than in matched normal tissue (“>=5×”); and 8) the percentage of patients tested in which expression levels (e.g., as message level) of the gene was less than or equal to ½ of the expression level in matched normal cells (“<=half×”).

Table 16 (on a CD ROM filed herewith) provides the results for gene products in which expression levels of the gene in prostate tumor cells was less than or equal to ½ of the expression level in normal tissue samples in at least 20% of the patients tested. Table 16 includes: 1) the spot identification number (“Spot ID”); 2) the GenBank Accession Number of the publicly available sequence corresponding to the polynucleotide (“GenBankHit”); 3) a description of the GenBank sequence (“GenBankDesc”); 4) the score of the similarity of the polynucleotide sequence and the GenBank sequence (“GenBankScore”); 5) the number of patients analyzed; 6) the percentage of patients tested in which expression levels (e.g., as message level) of the gene was at least 2-fold greater in cancerous tissue than in matched normal tissue (“>=2×”); 7) the percentage of patients tested in which expression levels (e.g., as message level) of the gene was at least 5-fold greater in cancerous tissue than in matched normal tissue (“>=5×”); and 8) the percentage of patients tested in which expression levels (e.g., as message level) of the gene was less than or equal to ½ of the expression level in matched normal cells (“<=half×”).

Tables 15 and 16 also include the results from each patient, identified by the patient ID number (e.g., 93). This data represents the ratio of differential expression for the samples tested from that particular patient's tissues (e.g., “93” is the ratio from the tissue samples of patient ID no. 93). The ratios of differential expression are expressed as a normalized hybridization signal associated with the tumor probe divided by the normalized hybridization signal with the normal probe. Thus, a ratio greater than 1 indicates that the gene product is increased in expression in cancerous cells relative to normal cells, while a ratio of less than 1 indicates the opposite.

These data provide evidence that the genes represented by the polynucleotides having the indicated sequences are differentially expressed in prostate cancer as compared to normal non-cancerous prostate tissue.

Example 21 Antisense Regulation of Gene Expression

The expression of the differentially expressed genes represented by the polynucleotides in the cancerous cells can be analyzed using antisense knockout technology to confirm the role and function of the gene product in tumorigenesis, e.g., in promoting a metastatic phenotype.

A number of different oligonucleotides complementary to the mRNA generated by the differentially expressed genes identified herein can be designed as potential antisense oligonucleotides, and tested for their ability to suppress expression of the genes. Sets of antisense oligomers specific to each candidate target are designed using the sequences of the polynucleotides corresponding to a differentially expressed gene and the software program HYBsimulator Version 4 (available for Windows 95/Windows NT or for Power Macintosh, RNAture, Inc. 1003 Health Sciences Road, West, Irvine, Calif. 92612 USA). Factors that are considered when designing antisense oligonucleotides include: 1) the secondary structure of oligonucleotides; 2) the secondary structure of the target gene; 3) the specificity with no or minimum cross-hybridization to other expressed genes; 4) stability; 5) length and 6) terminal GC content. The antisense oligonucleotide is designed so that it will hybridize to its target sequence under conditions of high stringency at physiological temperatures (e.g., an optimal temperature for the cells in culture to provide for hybridization in the cell, e.g., about 37° C.), but with minimal formation of homodimers.

Using the sets of oligomers and the HYBsimulator program, three to ten antisense oligonucleotides and their reverse controls are designed and synthesized for each candidate mRNA transcript, which transcript is obtained from the gene corresponding to the target polynucleotide sequence of interest. Once synthesized and quantitated, the oligomers are screened for efficiency of a transcript knock-out in a panel of cancer cell lines. The efficiency of the knock-out is determined by analyzing mRNA levels using lightcycler quantification. The oligomers that resulted in the highest level of transcript knock-out, wherein the level was at least about 50%, preferably about 80-90%, up to 95% or more up to undetectable message, are selected for use in a cell-based proliferation assay, an anchorage independent growth assay, and an apoptosis assay.

The ability of each designed antisense oligonucleotide to inhibit gene expression is tested through transfection into LNCaP, PC3, 22Rv1, MDA-PCA-2b, or DU145 prostate carcinoma cells. For each transfection mixture, a carrier molecule (such as a lipid, lipid derivative, lipid-like molecule, cholesterol, cholesterol derivative, or cholesterol-like molecule) is prepared to a working concentration of 0.5 mM in water, sonicated to yield a uniform solution, and filtered through a 0.45 μm PVDF membrane. The antisense or control oligonucleotide is then prepared to a working concentration of 100 μM in sterile Millipore water. The oligonucleotide is further diluted in OptiMEM™ (Gibco/BRL), in a microfuge tube, to 2 μM, or approximately 20 μg oligo/mil of OptiMEM™. In a separate microfuge tube, the carrier molecule, typically in the amount of about 1.5-2 nmol carrier/μg antisense oligonucleotide, is diluted into the same volume of OptiMEM™ used to dilute the oligonucleotide. The diluted antisense oligonucleotide is immediately added to the diluted carrier and mixed by pipetting up and down. Oligonucleotide is added to the cells to a final concentration of 30 nM.

The level of target mRNA that corresponds to a target gene of interest in the transfected cells is quantitated in the cancer cell lines using the Roche LightCycler™ real-time PCR machine. Values for the target mRNA are normalized versus an internal control (e.g., beta-actin). For each 20 μl reaction, extracted RNA (generally 0.2-1 μg total) is placed into a sterile 0.5 or 1.5 ml microcentrifuge tube, and water is added to a total volume of 12.5 μl. To each tube is added 7.5 μl of a buffer/enzyme mixture, prepared by mixing (in the order listed) 2.5 μl H₂O, 2.0 μl 10× reaction buffer, 10 μl oligo dT (20 pmol), 1.0 μl dNTP mix (10 mM each), 0.5 μl RNAsin® (20 u) (Ambion, Inc., Hialeah, Fla.), and 0.5 μl MMLV reverse transcriptase (50 u) (Ambion, Inc.). The contents are mixed by pipetting up and down, and the reaction mixture is incubated at 42° C. for 1 hour. The contents of each tube are centrifuged prior to amplification.

An amplification mixture is prepared by mixing in the following order: 1× PCR buffer II, 3 mM MgCl₂, 140 μM each dNTP, 0.175 pmol each oligo, 1:50,000 dil of SYBR® Green, 0.25 mg/ml BSA, 1 unit Taq polymerase, and H₂O to 20 μl. (PCR buffer II is available in 10× concentration from Perkin-Elmer, Norwalk, Conn.). In 1× concentration it contains 10 mM Tris pH 8.3 and 50 mM KCl. SYBR® Green (Molecular Probes, Eugene, Oreg.) is a dye which fluoresces when bound to double stranded DNA. As double stranded PCR product is produced during amplification, the fluorescence from SYBR® Green increases. To each 20 μl aliquot of amplification mixture, 2 μl of template RT is added, and amplification is carried out according to standard protocols. The results are expressed as the percent decrease in expression of the corresponding gene product relative to non-transfected cells, vehicle-only transfected (mock-transfected) cells, or cells transfected with reverse control oligonucleotides.

Example 22 Effect of Expression on Proliferation

The effect of gene expression on the inhibition of cell proliferation can be assessed in metastatic breast cancer cell lines (MDA-MB-231 (“231”)); SW620 colon colorectal carcinoma cells; SKOV3 cells (a human ovarian carcinoma cell line); or LNCaP, PC3, 22Rv1, MDA-PCA-2b, or DU145 prostate cancer cells.

Cells are plated to approximately 60-80% confluency in 96-well dishes. Antisense or reverse control oligonucleotide is diluted to 2 μM in OptiMEM™. The oligonucleotide-OptiMEM™ can then be added to a delivery vehicle, which delivery vehicle can be selected so as to be optimized for the particular cell type to be used in the assay. The oligo/delivery vehicle mixture is then further diluted into medium with serum on the cells. The final concentration of oligonucleotide for all experiments can be about 300 nM.

Antisense oligonucleotides are prepared as described above (see Example 21). Cells are transfected overnight at 37° C. and the transfection mixture is replaced with fresh medium the next morning. Transfection is carried out as described above in Example 21.

Those antisense oligonucleotides that result in inhibition of proliferation of SW620 cells indicate that the corresponding gene plays a role in production or maintenance of the cancerous phenotype in cancerous colon cells. Those antisense oligonucleotides that inhibit proliferation in SKOV3 cells represent genes that play a role in production or maintenance of the cancerous phenotype in cancerous breast cells. Those antisense oligonucleotides that result in inhibition of proliferation of MDA-MB-231 cells indicate that the corresponding gene plays a role in production or maintenance of the cancerous phenotype in cancerous ovarian cells. Those antisense oligonucleotides that inhibit proliferation in LNCaP, PC3, 22Rv1, MDA-PCA-2b, or DU145 cells represent genes that play a role in production or maintenance of the cancerous phenotype in cancerous prostate cells.

Example 23 Effect of Gene Expression on Cell Migration

The effect of gene expression on the inhibition of cell migration can be assessed in LNCaP, PC3, 22Rv1, MDA-PCA-2b, or DU145 prostate cancer cells using static endothelial cell binding assays, non-static endothelial cell binding assays, and transmigration assays.

For the static endothelial cell binding assay, antisense oligonucleotides are prepared as described above (see Example 21). Two days prior to use, prostate cancer cells (CaP) are plated and transfected with antisense oligonucleotide as described above (see Examples 21 and 22). On the day before use, the medium is replaced with fresh medium, and on the day of use, the medium is replaced with fresh medium containing 2 μM CellTracker green CMFDA (Molecular Probes, Inc.) and cells are incubated for 30 min. Following incubation, CaP medium is replaced with fresh medium (no CMFDA) and cells are incubated for an additional 30-60 min. CaP cells are detached using CMF PBS/2.5 mM EDTA or trypsin, spun and resuspended in DMEM/1% BSA/10 mM HEPES pH 7.0. Finally, CaP cells are counted and resuspended at a concentration of 1×10⁶ cells/ml.

Endothelial cells (EC) are plated onto 96-well plates at 40-50% confluence 3 days prior to use. On the day of use, EC are washed 1× with PBS and 50λ DMDM/1%BSA/10 mM HEPES pH 7 is added to each well. To each well is then added 50K (50λ) CaP cells in DMEM/1% BSA/10 mM HEPES pH 7. The plates are incubated for an additional 30 min and washed 5× with PBS containing Ca⁺⁺ and Mg⁺⁺. After the final wash, 100 μL PBS is added to each well and fluorescence is read on a fluorescent plate reader (Ab492/Em 516 nm).

For the non-static endothelial cell binding assay, CaP are prepared as described above. EC are plated onto 24-well plates at 30-40% confluence 3 days prior to use. On the day of use, a subset of EC are treated with cytokine for 6 hours then washed 2× with PBS. To each well is then added 150-200K CaP cells in DMEM/1% BSA/10 mM HEPES pH 7. Plates are placed on a rotating shaker (70 RPM) for 30 min and then washed 3× with PBS containing Ca⁺⁺ and Mg⁺⁺. After the final wash, 500 μL PBS is added to each well and fluorescence is read on a fluorescent plate reader (Ab492/Em 516 nm).

For the transmigration assay, CaP are prepared as described above with the following changes. On the day of use, CaP medium is replaced with fresh medium containing 5 μM CellTracker green CMFDA (Molecular Probes, Inc.) and cells are incubated for 30 min. Following incubation, CaP medium is replaced with fresh medium (no CMFDA) and cells are incubated for an additional 30-60 min. CaP cells are detached using CMF PBS/2.5 mM EDTA or trypsin, spun and resuspended in EGM-2-MV medium. Finally, CaP cells are counted and resuspended at a concentration of 1×10⁶ cells/ml.

EC are plated onto FluorBlok transwells (BD Biosciences) at 30-40% confluence 5-7 days before use. Medium is replaced with fresh medium 3 days before use and on the day of use. To each transwell is then added 50K labeled CaP. 30 min prior to the first fluorescence reading, 10 μg of FITC-dextran (10K MW) is added to the EC plated filter. Fluorescence is then read at multiple time points on a fluorescent plate reader (Ab492/Em 516 nm).

Those antisense oligonucleotides that result in inhibition of binding of LNCaP, PC3, 22Rv1, MDA-PCA-2b, or DU145 prostate cancer cells to endothelial cells indicate that the corresponding gene plays a role in the production or maintenance of the cancerous phenotype in cancerous prostate cells. Those antisense oligonucleotides that result in inhibition of endothelial cell transmigration by LNCaP, PC3, 22Rv1, MDA-PCA-2b, or DU145 prostate cancer cells indicate that the corresponding gene plays a role in the production or maintenance of the cancerous phenotype in cancerous prostate cells.

Example 24 Effect of Gene Expression on Colony Formation

The effect of gene expression upon colony formation of SW620 cells, SKOV3 cells, MD-MBA-231 cells, LNCaP cells, PC3 cells, 22Rv1 cells, MDA-PCA-2b cells, and DU145 cells can be tested in a soft agar assay. Soft agar assays are conducted by first establishing a bottom layer of 2 ml of 0.6% agar in media plated fresh within a few hours of layering on the cells. The cell layer is formed on the bottom layer by removing cells transfected as described above from plates using 0.05% trypsin and washing twice in media. The cells are counted in a Coulter counter, and resuspended to 10⁶ per ml in media. 10 μl aliquots are placed with media in 96-well plates (to check counting with WST1), or diluted further for the soft agar assay. 2000 cells are plated in 800 μl 0.4% agar in duplicate wells above 0.6% agar bottom layer. After the cell layer agar solidifies, 2 ml of media is dribbled on top and antisense or reverse control oligo (produced as described above) is added without delivery vehicles. Fresh media and oligos are added every 3-4 days. Colonies form in 10 days to 3 weeks. Fields of colonies are counted by eye. Wst-1 metabolism values can be used to compensate for small differences in starting cell number. Larger fields can be scanned for visual record of differences.

Those antisense oligonucleotides that result in inhibition of colony formation of SW620 cells indicate that the corresponding gene plays a role in production or maintenance of the cancerous phenotype in cancerous colon cells. Those antisense oligonucleotides that inhibit colony formation in SKOV3 cells represent genes that play a role in production or maintenance of the cancerous phenotype in cancerous breast cells. Those antisense oligonucleotides that result in inhibition of colony formation of MDA-MB-231 cells indicate that the corresponding gene plays a role in production or maintenance of the cancerous phenotype in cancerous ovarian cells. Those antisense oligonucleotides that inhibit colony formation in LNCaP, PC3, 22Rv1, MDA-PCA-2b, or DU145 cells represent genes that play a role in production or maintenance of the cancerous phenotype in cancerous prostate cells.

Example 25 Induction of Cell Death Upon Depletion of Polypeptides by Depletion of mRNA (“Antisense Knockout”)

In order to assess the effect of depletion of a target message upon cell death, LNCaP, PC3, 22Rv1, MDA-PCA-2b, or DU145 cells, or other cells derived from a cancer of interest, can be transfected for proliferation assays. For cytotoxic effect in the presence of cisplatin (cis), the same protocol is followed but cells are left in the presence of 2 μM drug. Each day, cytotoxicity is monitored by measuring the amount of LDH enzyme released in the medium due to membrane damage. The activity of LDH is measured using the Cytotoxicity Detection Kit from Roche Molecular Biochemicals. The data is provided as a ratio of LDH released in the medium vs. the total LDH present in the well at the same time point and treatment (rLDH/tLDH). A positive control using antisense and reverse control oligonucleotides for BCL2 (a known anti-apoptotic gene) is included; loss of message for BCL2 leads to an increase in cell death compared with treatment with the control oligonucleotide (background cytotoxicity due to transfection).

Example 26 Functional Analysis of Gene Products Differentially Expressed in Prostate Cancer in Patients

The gene products of sequences of a gene differentially expressed in cancerous cells can be further analyzed to confirm the role and function of the gene product in tumorigenesis, e.g., in promoting or inhibiting development of a metastatic phenotype. For example, the function of gene products corresponding to genes identified herein can be assessed by blocking function of the gene products in the cell. For example, where the gene product is secreted or associated with a cell surface membrane, blocking antibodies can be generated and added to cells to examine the effect upon the cell phenotype in the context of, for example, the transformation of the cell to a cancerous, particularly a metastatic, phenotype. In order to generate antibodies, a clone corresponding to a selected gene product is selected, and a sequence that represents a partial or complete coding sequence is obtained. The resulting clone is expressed, the polypeptide produced isolated, and antibodies generated. The antibodies are then combined with cells and the effect upon tumorigenesis assessed.

Where the gene product of the differentially expressed genes identified herein exhibits sequence homology to a protein of known function (e.g., to a specific kinase or protease) and/or to a protein family of known function (e.g., contains a domain or other consensus sequence present in a protease family or in a kinase family), then the role of the gene product in tumorigenesis, as well as the activity of the gene product, can be examined using small molecules that inhibit or enhance function of the corresponding protein or protein family.

Additional functional assays include, but are not necessarily limited to, those that analyze the effect of expression of the corresponding gene upon cell cycle and cell migration. Methods for performing such assays are well known in the art.

Example 27 Contig Assembly and Additional Gene Characterization

The sequences of the polynucleotides provided in the present invention can be used to extend the sequence information of the gene to which the polynucleotides correspond (e.g., a gene, or mRNA encoded by the gene, having a sequence of the polynucleotide described herein). This expanded sequence information can in turn be used to further characterize the corresponding gene, which in turn provides additional information about the nature of the gene product (e.g., the normal function of the gene product). The additional information can serve to provide additional evidence of the gene product's use as a therapeutic target, and provide further guidance as to the types of agents that can modulate its activity.

In one example, a contig is assembled using a sequence of a polynucleotide of the present invention, which is present in a clone. A “contig” is a contiguous sequence of nucleotides that is assembled from nucleic acid sequences having overlapping (e.g., shared or substantially similar) sequence information. The sequences of publicly-available ESTs (Expressed Sequence Tags) and the sequences of various clones from several cDNA libraries synthesized at Chiron can be used in the contig assembly.

The contig is assembled using the software program Sequencher, version 4.05, according to the manufacturer's instructions and an overview alignment of the contiged sequences is produced. The sequence information obtained in the contig assembly can then be used to obtain a consensus sequence derived from the contig using the Sequencher program. The consensus sequence is used as a query sequence in a TeraBLASTN search of the DGTI DoubleTwist Gene Index (DoubleTwist, Inc., Oakland, Calif.), which contains all the EST and non-redundant sequence in public databases.

Through contig assembly and the use of homology searching software programs, the sequence information provided herein can be readily extended to confirm, or confirm a predicted, gene having the sequence of the polynucleotides described in the present invention. Further the information obtained can be used to identify the function of the gene product of the gene corresponding to the polynucleotides described herein. While not necessary to the practice of the invention, identification of the function of the corresponding gene, can provide guidance in the design of therapeutics that target the gene to modulate its activity and modulate the cancerous phenotype (e.g., inhibit metastasis, proliferation, and the like).

Example 28 Expression of chondroitin 4-O sulfotransferase 2 (C4S-2)

Laser Capture Microdissection (LCM) was used to dissect cancerous cells, as well as peri-tumoral normal cells from patients with prostate cancer (various grades), colon cancer, breast cancer and stomach cancer. Total RNA was prepared from these samples by standard methods. cDNA probes were made from this RNA and fluorescently labeled. The labeled cDNAs were used to probe a microarray chip containing sequences of multiple genes. As shown in Table. 15, Spot ID 25837, which corresponds to chondroitin 4-O sulfotransferase 2 (C4S-2) and SEQ ID 847 (see Table 14), revealed a differential expression between normal and cancerous cells. The data displayed in FIG. 22 show an up-regulation of C4S-2 mRNA in prostate, colon and stomach cancer. The table headings are as follows: “# Patients” indicates the number of patients whose RNA was analyzed for each cancer type, and the percentages of each of the patient groups is expressed in the table; “>2×” indicates a greater than two-fold up-regulation (cancer over normal) at the mRNA level; “>5×” indicates a greater than 5-fold up-regulation at the mRNA level; “<0.5×” indicates a greater than 2-fold down-regulation at the mRNA level. Further experimental details of this example may be found in Example 20 of this disclosure.

Trending analysis revealed that several genes trend in patient expression with C4S-2 (FIG. 34). These genes may have significance in pathways, both upstream and downstream of C4S-2.

Example 29 C4S-2 mRNA Expression in Laser Capture Microdissected Tissues

Quantitative PCR of a number of normal tissues and tumor cell lines, particularly colorectal and prostate carcinoma cell lines was used to analyze expression of C4S2. Quantitative real-time PCR was performed by first isolating RNA from cells using a Roche RNA Isolation kit according to manufacturer's directions. One microgram of RNA was used to synthesize a first-strand cDNA using MMLV reverse transcriptase (Ambion) using the manufacturers buffer and recommended concentrations of oligo dT, nucleotides, and Rnasin.

First, primers were designed. The primers were blasted against known genes and sequences to confirm the specificity of the primers to the target. The sequences of the primers are, for set 1: Forward: ATCTCCGCCTTCCGCAGCAA and reverse: TCGTTGAAGGGCGCCAGCTT, and set 2: Forward: CCATCTACTGCTACGTG and reverse: ACTTCTTGAGCTTGACC. These primers were used in a test qPCR using the primers against normal RTd tissue, as well as a mock RT to pick up levels of possible genomic contamination.

Quantitative PCR of a panel of normal tissue, total cancer tissue, LCM tissue, and cancer cell lines were used to determine the expression levels of C4S2. qPCR was performed by first isolating the RNA from the above mentioned tissue/cells using a Qiagen RNeasy mini prep kit. In the case of the LCM tissue, RNA was amplified via PCR to increase concentration after initial RNA isolation. 0.5 micrograms of RNA was used to generate a first strand cDNA using Stratagene MuLV Reverse Transcriptase, using recommended concentrations of buffer, enzyme, and Rnasin. Concentrations and volumes of dNTP, and oligo dT, or random hexamers were lower than recommended to reduce the level of background primer dimerization in the qPCR.

The cDNA is then used for qPCR to determine the levels of expression of C4S2 using the GeneAmp 7000 by ABI as recommended by the manufacturer. Primers for housekeeping were also run in order to normalized the values, and eliminate possible variations in cDNA template concentrations, pipetting error, etc. Three housekeepers were run depending on the type of tissue, beta-actin for cell lines, GusB for LCM tissue, HPRT for whole tissue.

A subset of patient RNA used to probe the microarray chip was analyzed by semi-quantitative RT-PCR to confirm the microarray results. Pools of 7 or 8 patient RNA samples were analyzed using primers that specifically recognize C4S-2. The data is expressed as mRNA expression level relative to a housekeeping gene (GUSB). Consistent with the microarray data, the data, displayed in FIG. 23, show an up-regulation of C4S-2 mRNA in prostate and colon cancer and a down-regulation in breast cancer. Furthermore, the data reveal that peri-tumoral normal cells in high grade prostate cancer display an elevated expression relative to peri-tumoral normal cells in low grade prostate cancer, suggesting a global up-regulation of C4S-2 mRNA with progression in grade. “(2×)” indicates RNA was amplified two times; “N” indicates peri-tumoral normal epithelial cells; “C” indicates cancerous epithelial cells; “LG” indicates low grade; “HG” indicates high grade.

Example 30 C4S-2 mRNA Expression in Tissue Samples

Using the RT-PCR methods described above, C4S-2 specific primers were used to assess the expression of C4S-2 mRNA obtained from normal tissues (from commercial sources), as well as RNA expression whole tumor tissue (pools of 7 or 8 patients). This tissue contains cell types other than epithelium. The data is expressed as mRNA expression level relative to a housekeeping gene (HPRT). The data, shown in FIG. 24, reveal that C4S-2 mRNA is ubiquitously expressed, throughout the body, with highest expression in normal adrenal, lung and breast tissue. The data further reveal significant expression in colon and prostate cancer (marked with a “C”) and down-regulation in breast cancer, relative to normal breast tissue.

Example 31 C4S-2 mRNA Expression in Prostate Cell Lines

Using the RT-PCR methods described above, C4S-2 specific primers were used to assess the expression of C4S-2 mRNA obtained from various prostate cell lines. The data is expressed as mRNA expression level relative to a housekeeping gene (actin). The data, displayed in FIG. 25, show that C4S-2 mRNA is expressed at higher levels in cell lines derived from prostate cancer tumors than in cell lines derived from normal prostate epithelium.

Example 32 Antisense Regulation of C4S-2 Expression

Additional functional information on C4S-2 was generated using antisense knockout technology. A number of different oligonucleotides complementary to C4S-2 mRNA were designed (FIG. 26) as potential antisense oligonucleotides, and tested for their ability to suppress expression of C4S-2. For each transfection mixture, a carrier molecule, preferably a lipitoid or cholesteroid, was prepared to a working concentration of 0.5 mM in water, sonicated to yield a uniform solution, and filtered through a 0.45 μm PVDF membrane. The antisense or control oligonucleotide was then prepared to a working concentration of 100 μM in sterile Millipore water. The oligonucleotide was further diluted in OptiMEM™ (Gibco/BRL), in a microfuge tube, to 2 μM, or approximately 20 μg oligo/ml of OptiMEM™. In a separate microfuge tube, lipitoid or cholesteroid, typically in the amount of about 1.5-2 nmol lipitoid/gg antisense oligonucleotide, was diluted into the same volume of OptiMEM™ used to dilute the oligonucleotide. The diluted antisense oligonucleotide was immediately added to the diluted lipitoid and mixed by pipetting up and down. Oligonucleotide was added to the cells to a final concentration of 30 nM.

The level of target mRNA (C4S-2) in the transfected cells was quantitated in the cancer cell lines using the methods described above. Values for the target mRNA were normalized versus an internal control (e.g., beta-actin). For each 20 μl reaction, extracted RNA (generally 0.2-1 μg total) was placed into a sterile 0.5 or 1.5 ml microcentrifuge tube, and water was added to a total volume of 12.5 μl. To each tube was added 7.5 μl of a buffer/enzyme mixture, prepared by mixing (in the order listed) 2.5 μl H₂O, 2.0 μl 10× reaction buffer, 10 μl oligo dT (20 pmol), 1.0 μl dNTP mix (10 mM each), 0.5 μl RNAsin® (20u) (Ambion, Inc., Hialeah, Fla.), and 0.5 μl MMLV reverse transcriptase (50 u) (Ambion, Inc.). The contents were mixed by pipetting up and down, and the reaction mixture was incubated at 42° C. for 1 hour. The contents of each tube were centrifuged prior to amplification.

An amplification mixture was prepared by mixing in the following order: 1×PCR buffer II, 3 mM MgCl₂, 140 μM each dNTP, 0.175 pmol each oligo, 1:50,000 dil of SYBR® Green, 0.25 mg/ml BSA, 1 unit Taq polymerase, and H₂O to 20 μl. (PCR buffer II is available in 10× concentration from Perkin-Elmer, Norwalk, Conn.). In 1× concentration it contains 10 mM Tris pH 8.3 and 50 mM KCl. SYBR® Green (Molecular Probes, Eugene, Oreg.) is a dye which fluoresces when bound to double stranded DNA. As double stranded PCR product is produced during amplification, the fluorescence from SYBR® Green increases. To each 20 μl aliquot of amplification mixture, 2 μl of template RT was added, and amplification was carried out according to standard protocols.

FIG. 26 shows examples of anti-sense oligonucleotide sequences that inhibit C4S-2 mRNA expression when transfected into cells. Functional data described in the following examples was obtained using C210-3,4 & 6. C4S-2 mRNA reduction ranged from about 60 to about 90%, as compared to cells transfected with reverse (i.e. sense) control oligonucleotides.

In separate experiments, inhibitory RNA molecules are used to inhibit C4S-2 mRNA expression in cells. FIG. 27 lists inhibitory RNA oligonucleotides that may be used in these experiments.

Example 33 Effects of C4S-2 Antisense Molecules on Cellular Proliferation

PC3 cells were plated at 5000 cells/well in 96-well plate and grown overnight. Reverse control or antisense oligonucleotide was diluted to 2 μM in OptiMEM™ and mixed with 30 μM Lipitoid1, a delivery vehicle, also diluted in OptiMEM™. This mixture of oligonucleotide and lipitoid in OptiMEM™ was then mixed with serum containing medium and then overlayed onto the cells overnight. The next day the transfection mix was removed and replaced with fresh media. Final concentration of oligonucleotide for these experiments was 300 nM and the ratio of oligonucleotide to Lipitoid 1 was 1.5 nmol lipoid per μg oligonucleotide. Cell proliferation was quantified using CyQUANT® Cell Proliferation Assay Kit (Molecular Probes #C-7026).

MDAPca2b cells were plated to 50% confluency and similarly transfected with 300 nM reverse control or antisense oligonucleotide with 30 μM Lipitoid1 overnight. After transfection, the cells were detached with trypsin, washed twice with medium, counted and plated at 5000 cells/well in 96-well plates. Cell proliferation was quantified using CellTiter-Glo™ Luminescent Cell Viability Assay (Promega #G7573).

Using these methods, anti-sense oligonucleotides described in FIG. 26 were transfected into PC3 cells. This usually resulted in a 60-90% knockdown of C4S-2 mRNA compared to controls. As controls, cells were left either untreated or were transfected with reverse control oligonucleotides. The cells were assessed for their ability to grow on tissue culture plastic in a time course that spanned 7 days. The number of cells on any given day was assessed using either the CyQuant assay or the luciferase assay. As shown in the two repeats of the same experiment described in FIG. 28, the ability of PC3 cells to grow in vitro is inhibited by anti-sense oligonucleotides that inhibit C4S-2 expression.

Anti-sense oligonucleotides described in FIG. 26 were transfected into MDA Pca 2b cells. This resulted in a 60-90% knockdown of C4S-2 mRNA. As controls, cells were left either untreated or were transfected with reverse control oligonucleotides. The cells were assessed for their ability to grow on tissue culture plastic in a time course that spanned 7 days. The number of cells on any given day was assessed using either the CyQuant assay or the luciferase assay (depending on the experiment). As shown in FIG. 29, the ability of MDA Pca 2b cells to grow in vitro is inhibited by anti-sense oligonucleotides that inhibit C4S-2 expression (“RC” is a control oligonucleotide; measurements 1, 2 and 3 were taken on three days).

Example 34 Effects of C4S-2 Antisense Molecules on Colony Formations

The effect of C4S-2 expression upon colony formation was tested in a soft agar assay. Soft agar assays were conducted by first establishing a bottom layer of 2 ml of 0.6% agar in media plated fresh within a few hours of layering on the cells. The cell layer was formed on the bottom layer by removing cells transfected as described above from plates using 0.05% trypsin and washing twice in media. The cells were counted in a Coulter counter, and resuspended to 10⁶ per ml in media. 10 μl aliquots are placed with media in 96-well plates (to check counting with WST1), or diluted further for soft agar assay. 2000 cells are plated in 800 μl 0.4% agar in duplicate wells above 0.6% agar bottom layer. After the cell layer agar solidifies, 2 ml of media is dribbled on top and antisense or reverse control oligo is added-without delivery vehicles. Fresh media and oligos are added every 3-4 days. Colonies are formed in 10 days to 3 weeks. Fields of colonies were counted by eye.

PC3 cells were transfected as described above. Transfected cells were then assessed for their ability to grow in soft-agar to determine the effect of inhibiting C4S-2 on anchorage-independent growth. PC3 cells were plated at either 400, 600 or 1000 (“1 k”)cells per well. Multiple transfection conditions were used (L1 or L1/C1). As shown in FIG. 30, PC3 cells transfected with C4S-2 anti-sense oligos consistently yielded fewer colonies than those transfected with reverse control oligos. “UT” denotes untransfected cells; “RC” denotes transfected with reverse control oligos; “AS” denotes transfected with anti-sense oligos;

MDA Pca 2b cells were transfected as described above and also assessed for their ability to grow in soft-agar to determine the effect of inhibiting C4S-2 on anchorage-independent growth. MDA Pca 2b cells were plated at either 400, 600 or 1000 cells per well. As shown in FIG. 31, MDA Pca 2b cells transfected with C4S-2 anti-sense oligos consistently yielded fewer colonies than those transfected with reverse control oligos.

Example 34 Effects of C4S-2 Antisense Molecules on Spheroids

Spheroids were assayed as follows: briefly, 96-well plates were coated with poly(2-hydroxyethyl methacrylate or poly-HEMA at 12 ug/ml in 95% ethanol. Poly-HEMA was slowly evaporated at room temperature until plates were dry. Prior to adding cells plates were rinsed twice with 1× PBS. Approximately 10 000 cells/well were then added and transfected with either anti-sense or reverse control oligonucleotide, directly in suspension with similar conditions as described elsewhere. The cells were allowed to grow in suspension for 5 days. The effects of inhibiting C4S-2 mRNA expression were assessed both visually and using the LDH assay to assess degree of cytotoxicity.

Lactate dehydrogenase (LDH) activity is measured, using the Cytotoxicity Detection Kit (Roche Catalog number: 1 644 793) by collecting culture supernatant and adding 100 ul ALPHA MEM medium w/o FBS in V-bottom 96 well plate, transferring all the culture supernatant (100 ul) to the V-bottom plate, mixing, spinning the plate at 2000 rpm for 10 mins, and removing 100 μl for an LDH assay. Alternatively, culture supernatant was removed, and 200 ul ALPHA MEM medium w/o FBS and containing 2% Triton-X 100 was added to the plate, incubated for 1 minute to all for lysis, spun at 2000 rpm for 10 min and 100 μl removed for LDH detection.

LDH was measured using a 1:45 mixture of catalyst, diaphoreses/NAD⁺ mixture, lyophilizate resuspended H₂O and dye solution containing sodium lactate, respectively. 100 ul of this mix is added to each well, and the sample incubated at room temperature for 20 mins. Plates can be reat in a microtiter plate reader with 490 nm filter.

rLDH/tLDH ratio is calculated as follows: the total amount of LDH (tLDH) is calculated by adding released LDH (rLDH, from culture supernatant) to the intracellular LDH (iLDH, from cell lysate): tLDH=rLDH+iLDH. In order to compare the amount of cytotoxicity between AS and RC treated samples, the ratio between rLDH and tLDH is used.

MDA Pca 2b were plated under non-adherent conditions and transfected in suspension with either anti-sense or reverse control oligonucleotides. The cells were allowed to grow in suspension for 5 days. The effects of inhibiting C4S-2 mRNA expression were assessed both visually (FIG. 32A-C) and using the LDH assay to assess degree of cytotoxicity (FIG. 32D). Inhibiting C4S-2 mRNA expression inhibited the ability of MDA Pca 2b to grow in suspension and furthermore, induced cytotoxicity.

Example 35 Effects of C4S-2 Antisense Molecules on Cytoxicity

Cells were transfected, and the activity of LDH was measured using the Cytotoxicity Detection Kit from Roche Molecular Biochemicals, as described above. The data is provided as a ratio of LDH released in the medium vs. the total LDH present in the well at the same time point and treatment (rLDH/tLDH). MRC9 cells were transfected with multiple pairs of C4S-2 anti-sense and reverse control oligonucleotides and allowed to grow for 3 days. The C4S-2 anti-sense oligonucleotides did not induce cytoxicity (above reverse control) in this “normal” (i.e. non-cancerous) fibroblast cell line (FIG. 33A). Controls antisense molecules, such as those for Bcl2, induced cytotoxicity. mRNA levels were also measured (FIG. 33B), showing that C4S-2 mRNA expression is lower in these cells than in other cells, and that no morphological differences in the antisensed cells as compared to control cells were observed (FIG. 33C).

184B5 cells were also transfected with multiple pairs of C4S-2 anti-sense and reverse control oligonucleotides and allowed to grow for 3 days. The C4S-2 anti-sense oligonucleotides did not induce cytoxicity (above reverse control) in this “normal” (i.e. non-cancerous) breast epithelial cell line (FIG. 34).

Example 36 Effects of C4S-2 Antisense Molecules on Poliferation of Normal Cells

MRC9 and 184B5 cells were transfected with multiple pairs of C4S-2 anti-sense and reverse control oligonucleotides and allowed to grow for 4 days. The C4S-2 anti-sense oligonucleotides did not inhibit proliferation (above reverse control) in these non-cancerous cell lines (FIG. 35).

Example 37 Screening Assays

Screening assays are performed according to Burkart & Wong Anal Biochem 274:131-137 (1999), with modifications.

Using primers flanking the open reading frame, C4S-2 is cloned into a shuttle vector, from which it can be shuttled into multiple expression vectors. Protein expression is assessed using a polyclonal antibody. Activity is assessed using standard assays, i.e. those designed to assay sulfate transfer to chondroitin, chondroitin sulfate or dermatan sulfate. βAST-IV is also cloned and expressed as described in the above report Burkart et al, supra.

C4S-2-modulatory agents are counter-screened to ensure specificity. Included in the counterscreen are C4S-1, C4S-3 and HNK1ST (closest relatives to C4S-2 with approximately 30-42% homology). Additionally, representatives from other classes of sulfotransferases (heparin sulfotransferase, estrogen sulfotransferase, phenol sulfotransferase, tyrosine sulfotransferase) with low homology are also screened. Additionally, representatives from classes of kinases will be used in the counter-screen.

C4S-2 will transfer a sulfonyl group from PAPS to chondroitin sulfate, thus generating PAP. βAST-IV will regenerate PAPS, using p-nitrophenyl sulfate as the sulfate donor. One of the resulting products from the latter reaction—p-nitrophenol can be monitored colorimetrically.

Inhibitors are assessed for their ability to inhibit C4S-2, as determined by an inhibition of p-nitrophenol generation. Control screens include regeneration of PAPS from PAP by βAST-IV, in the absence of C4S-2, to ensure that inhibitors of βAST-IV are not selected. Compounds that inhibit C4S-2 activity are counterscreened against relevant enzymes listed above.

Inhibitors passing the above screens are tested in cell-based functional assays (Proliferation, LDH, spheroid and soft-agar assays). The tested cell lines include PC3, MDA Pca 2b, DU145, Colo320, KM12C, A431, MDA435, MDA469, etc. Additionally, cell lines stably transfected to over-express C4S-2 are assessed compared to parental and control transfected lines.

Inhibitors that show efficacy in the cell line functional assays are tested in xenograft mouse models. A subset of the lines, including PC3, DU145 and MDA435, etc. is in these animal models.

Example 38 Source of Biological Materials

The cells used for detecting differential expression of breast cancer related genes were those previously described for the HMT-3522 tumor reversion model, disclosed in U.S. Pat. Nos. 5,846,536 and 6,123,941, herein incorporated by reference. The model utilizes both non-tumorigenic (HMT-3522 S1) and tumorigenic (HMT-3522 T4-2) cells derived by serial passaging from a single reduction mammoplasty. In two dimensional (2D) monolayers on plastic, both S1 and T4-2 cells display similar morphology. But in three dimensional (3D) matrigel cultures, S1 form phenotypically normal mammary tissue structures while T4-2 cells fail to organize into these structures and instead disseminate into the matrix. This assay was designated as a tumor reversion model, in that the T4-2 cells can be induced to form S1-like structures in 3D by treatment with beta-1 integrin or EGFR blocking antibodies, or by treating with a chemical inhibitor of the EGFR signaling pathway (tyrophostin AG 1478). These treated T4-2 cells, called T4R cells, are non-tumorigenic.

Example 39 Cell Growth and RNA Isolation

Growth of Cells 2D and 3D for Microarray Experiments: HMT3522 S1 and T4-2 cells were grown 2D and 3D and T4-2 cells reverted with anti-EGFR, anti-beta 1 integrin, or tyrophostin AG 1478 as previously described (Weaver et al J Cell Biol. 137:231-45, 1997; and Wang et al PNAS 95:14821-14826, 1998). Anti-EGFR (mAb 225) was purchased from Oncogene and introduced into the matrigel at the time of gelation at a concentration of 4 ug/ml purified mouse IgG1. Anti-beta 1 integrin (mAb AIIB2) was a gift from C. Damsky at the University of California at San Francisco and was also introduced into the matrigel at the time of gelation at a concentration of 100 ug/ml ascites protein (which corresponds to 4-10 ug/ml purified rat IgG1). Tyrophostin AG 1478 was purchased from Calbiochem and used at a concentration of 100 nM.

Isolation of RNA for Microarray Experiments: RNA was prepared from: S1 passage 60 2D cultures; T4-2 passage 41 2D cultures; S1 passage 59 3D cultures; and T4-2 and T4-2 revertant (with anti-EGFR, anti-beta 1 integrin, and tyrophostin) passage 35 3D cultures.

All RNA for microarray experiments was isolated using the commercially available RNeasy Mini Kit from Qiagen. Isolation of total RNA from cells grown 2D was performed as instructed in the kit handbook. Briefly, media was aspirated from the cells and kit Buffer RLT was added directly to the flask. The cell lysate was collected with a rubber cell scraper, and the lysate passed 5 times through a 20-G needle fitted to a syringe. One volume of 70% ethanol was added to the homogenized lysate and mixed well by pipetting. Up to 700 ul of sample was applied to an RNeasy mini spin column sitting in a 2-ml collection tube and centrifuged for 15 seconds at >8000×g. 700 ul Buffer RW1 was added to the column and centrifuged for 15 seconds at >8000×g to wash. The column was transferred to a new collection tube. 500 ul Buffer RPE was added to the column and centrifuged for 15 seconds at >8000×g to wash. Another 500 ul Buffer RPE was added to the column for additional washing, and the column centrifuged for 2 minutes at maximum speed to dry. The column was transferred to a new collection tube and RNA eluted from the column with 30 ul RNase-free water by centrifuging for 1 minute at >8000×g.

Isolation of total RNA from cells grown 3D was performed as described above, except cells were isolated from matrigel prior to RNA isolation. The cells were isolated as colonies from matrigel using ice-cold PBS/EDTA (0.01 M sodium phosphate pH 7.2 containing 138 mM sodium chloride and 5 mM EDTA). See Weaver et al, J Cell Biol 137:231-245, 1997; and Wang et al. PNAS 95:14821-14826, 1998.

Example 40 Detection and Identification of Genes Exhibiting Differential Expression

The relative expression levels of a selected sequence (which in turn is representative of a single transcript) were examined in the tumorigenic versus non-tumorigenic cell lines described above, following culturing of the cells (S1, T4-2 and T4R) in either two-dimensional (2D) monolayers or three-dimensional (3D) matrigel cultures as described above. Differential expression for a selected sequence was assessed by hybridizing mRNA from S1 and T4-2 2D cultures, and S1, T4-2 and T4R 3D cultures to microarray chips as described below, as follows: Exp1=T4-2 2D/S1 2D; Exp2=T4-2 3D/S1 3D; Exp3=S1 3D/S1 2D; Exp4=T4-2 3D/T4-2 2D; Exp5=T4-2 3D/T4R (anti-EGFR) 3D; Exp6=T4-2 3D/T4R (anti-betal integrin) 3D; and Exp7=T4-2 3D/T4R (tyrophostin AG 1478) 3D.

Each array used had an identical spatial layout and control spot set. Each microarray was divided into two areas, each area having an array with, on each half, twelve groupings of 32×12 spots for a total of about 9,216 spots on each array. The two areas are spotted identically which provide for at least two duplicates of each clone per array. Spotting was accomplished using PCR amplified products from 0.5 kb to 2.0 kb and spotted using a Molecular Dynamics Gen III spotter according to the manufacturer's recommendations. The first row of each of the 24 regions on the array had about 32 control spots, including 4 negative control spots and 8 test polynucleotides.

The test polynucleotides were spiked into each sample before the labeling reaction with a range of concentrations from 2-600 pg/slide and ratios of 1:1. For each array design, two slides were hybridized with the test samples reverse-labeled in the labeling reaction. This provided for about 4 duplicate measurements for each clone, two of one color and two of the other, for each sample.

Identification Of Differentially Expressed Genes: “Differentially expressed” in the context of the present example meant that there was a difference in expression of a particular gene between tumorigenic vs. non-tumorigenic cells, or cells grown in three-dimensional culture vs. cells grown in two-dimensional culture. To identify differentially expressed genes, total RNA was first reverse transcribed into cDNA using a primer containing a T7 RNA polymerase promoter, followed by second strand DNA synthesis. cDNA was then transcribed in vitro to produce antisense RNA using the T7 promoter-mediated expression (see, e.g., Luo et al. (1999) Nature Med 5:117-122), and the antisense RNA was then converted into cDNA. The second set of cDNAs were again transcribed in vitro, using the T7 promoter, to provide antisense RNA. Optionally, the RNA was again converted into cDNA, allowing for up to a third round of T7-mediated amplification to produce more antisense RNA. Thus the procedure provided for two or three rounds of in vitro transcription to produce the final RNA used for fluorescent labeling.

Fluorescent probes were generated by first adding control RNA to the antisense RNA mix, and producing fluorescently labeled cDNA from the RNA starting material. Fluorescently labeled cDNAs prepared from tumorigenic RNA sample were compared to fluorescently labeled cDNAs prepared from non-tumorigenic cell RNA sample. For example, the cDNA probes from the non-tumorigenic cells were labeled with Cy3 fluorescent dye (green) and the cDNA probes prepared from the tumorigenic cells were labeled with Cy5 fluorescent dye (red).

The differential expression assay was performed by mixing equal amounts of probes from tumorigenic cells and non-tumorigenic cells, and/or cells grown in 3D vs. those grown in 2D. The arrays were prehybridized by incubation for about 2 hrs at 60° C. in 5×SSC/0.2% SDS/1 mM EDTA, and then washed three times in water and twice in isopropanol. Following prehybridization of the array, the probe mixture was then hybridized to the array under conditions of high stringency (overnight at 42° C. in 50% formamide, 5×SSC, and 0.2% SDS). After hybridization, the array was washed at 55° C. three times as follows: 1) first wash in 1×SSC/0.2% SDS; 2) second wash in 0.1×SSC/0.2% SDS; and 3) third wash in 0.1×SSC.

The arrays were then scanned for green and red fluorescence using a Molecular Dynamics Generation III dual color laser-scanner/detector. The images were processed using BioDiscovery Autogene software, and the data from each scan set normalized to provide for a ratio of expression relative to non-tumorigenic or tumorigenic cells grown two-dimensionally or three-dimensionally. Data from the microarray experiments was analyzed according to the algorithms described in U.S. application Ser. No. 60/252,358, filed Nov. 20, 2000, by E. J. Moler, M. A. Boyle, and F. M. Randazzo, and entitled “Precision and accuracy in cDNA microarray data,” which application is specifically incorporated herein by reference.

The experiment was repeated, this time labeling the two probes with the opposite color in order to perform the assay in both “color directions.” Each experiment was sometimes repeated with two more slides (one in each color direction). The level fluorescence for each sequence on the array expressed as a ratio of the geometric mean of 8 replicate spots/genes from the four arrays or 4 replicate spots/gene from 2 arrays or some other permutation. The data were normalized using the spiked positive controls present in each duplicated area, and the precision of this normalization was included in the final determination of the significance of each differential. The fluorescence intensity of each spot was also compared to the negative controls in each duplicated area to determine which spots have detected significant expression levels in each sample.

A statistical analysis of the fluorescent intensities was applied to each set of duplicate spots to assess the precision and significance of each differential measurement, resulting in a p-value testing the null hypothesis that there is no differential in the expression level between the tumorigenic and non-tumorigenic cells or cells grown two-dimensionally versus three-dimensionally. During initial analysis of the microarrays, the hypothesis was accepted if p>10⁻³, and the differential ratio was set to 1.000 for those spots. All other spots have a significant difference in expression between the two samples compared. For example, if the tumorigenic sample has detectable expression and the non-tumorigenic does not, the ratio is truncated at 1000 since the value for expression in the non-tumorigenic sample would be zero, and the ratio would not be a mathematically useful value (e.g., infinity). If the non-tumorigenic sample has detectable expression and the tumorigenic does not, the ratio is truncated to 0.001, since the value for expression in the tumor sample would be zero and the ratio would not be a mathematically useful value. These latter two situations are referred to herein as “on/off.” Database tables were populated using a 95% confidence level (p>0.05).

In general, a polynucleotide is said to represent a significantly differentially expressed gene between two samples when there is detectable levels of expression in at least one sample and the ratio value is greater than at least about 1.2 fold, at least about 1.5 fold, or at least about 2 fold, where the ratio value is calculated using the method described above.

A differential expression ratio of 1 indicates that the expression level of the gene in tumorigenic cells was not statistically different from expression of that gene in the specific non-tumorigenic cells compared. A differential expression ratio significantly greater than 1 in tumorigenic breast cells relative to non-tumorigenic breast cells indicates that the gene is increased in expression in tumorigenic cells relative to non-tumorigenic cells, suggesting that the gene plays a role in the development of the tumorigenic phenotype, and may be involved in promoting metastasis of the cell. Detection of gene products from such genes can provide an indicator that the cell is cancerous, and may provide a therapeutic and/or diagnostic target. Likewise, a differential expression ratio significantly less than 1 in tumorigenic breast cells relative to non-tumorigenic breast cells indicates that, for example, the gene is involved in suppression of the tumorigenic phenotype. Increasing activity of the gene product encoded by such a gene, or replacing such activity, can provide the basis for chemotherapy. Such gene can also serve as markers of cancerous cells, e.g., the absence or decreased presence of the gene product in a breast cell relative to a non-tumorigenic breast cell indicates that the cell is cancerous.

Using the above methodology, three hundred and sixty-seven (367) genes or products thereof were identified from 20,000 chip clones analyzed as being overexpressed 2-fold or more in one or more of these experiments, with a p-value of 0.001 or less. These identified genes or products thereof are listed in Table 17, according to the Spot ID of the spotted polynucleotide, the Sample ID, the corresponding GenBank Accession Number (No.), the GenBank description (if available) for the corresponding Genbank Accession Number, and the GenBank score (p-value; the probability that the association between the SEQ ID NO. and the gene or product thereof occurred by chance). The polynucleotide and polypeptide sequences, as provided by any disclosed Genbank entries are herein incorporated by reference to the corresponding Genbank accession number. The differential hybridization results from the seven differential expression microarray experiments listed above are provided in Table 18, where sequences have a measurement corresponding to its ratio of expression in the 7 experiments, e.g. spot ID 10594 is 2.2-fold overexpressed in 3D T4-2 cells as compared to 3D S1 cells. SEQ ID NOS:1-3004, representing the sequences corresponding to the spot Ids listed in Tables 17 and 18 are provided in the sequence listing. Table 27 is a lookup table showing the relationship between the spot Ids (i.e. the nucleic acids spotted on the microarray) and the sequences provided in the sequence listing. TABLE 17 GENBANK GENBANK SPOTID SAMPLE ID NO GENBANK DESCRIPTION SCORE 10594 I:1871362:05B01:A04 M62994 Homo sapiens thyroid autoantigen 8.6E−36  (truncated actin-binding protein) mRNA, complete cds 21851 M00055153A:A12 20990 I:1986550:13B02:G12 XM_005667 Homo sapiens lipocalin 2 0 (oncogene 24p3) (LCN2), mRNA 18641 I:3473302:09A01:A09 AB046098 Macaca fascicularis brain cDNA, 5.8E−57  clone: QccE-15843 17229 I:1506962:09A01:G01 AL365454 Homo sapiens mRNA full length 2.6E−110 insert cDNA clone EUROIMAGE 926491 25930 035JN020.F01 AJ010446 Homo sapiens mRNA for 0 immunoglobulin kappa light chain, anti-RhD, therad 24 20701 RG:730349:10010:G12 U28387 Human hexokinase II pseudogene, 0 complete cds 20346 RG:1839794:10015:E11 U28387 Human hexokinase II pseudogene, 0 complete cds 21247 M00054680C:A06 U28387 Human hexokinase II pseudogene, 9.9E−80  complete cds 23062 M00056353C:E10 XM_011013 Homo sapiens filamin B, beta 0 (actin-binding protein-278) (FLNB), mRNA 25666 035Jn031.B01 AF191633 Homo sapiens filamin (FLNB) 0 gene, exon 48 and complete cds 19001 I:2171401:09A02:E09 AF123887 Homo sapiens ERO1L (ERO1L) 3.3E−104 mRNA, partial cds 10897 I:1852047:02A01:A10 U22384 Human lysyl oxidase gene, partial 0 cds 1960 M00023297B:A10 M33376 Human pseudo-chlordecone 0 reductase mRNA, complete cds 26381 035JN029.H02 AB037838 Homo sapiens mRNA for 0 KIAA1417 protein, partial cds 26719 035JN030.A02 X68277 H. sapiens CL 100 mRNA for 0 protein tyrosine phosphatase 27152 037XN007.A09 XM_048479 Homo sapiens hypothetical protein 7.3E−58  FLJ14642 (FLJ14642), mRNA 10926 I:2047770:08B02:G04 AK000969 Homo sapiens cDNA FLJ10107 fis, 3.8E−94  clone HEMBA1002583 28980 035JN003.C12 XM_027456 Homo sapiens hypothetical gene 0 supported by AK000584 (LOC89942), mRNA 1236 M00022024A:F02 29350 035JN008.D06 XM_043864 Homo sapiens phosphoinositide-3- 0 kinase, regulatory subunit, polypeptide 1 (p85 alpha) (PIK3R1), mRNA 26242 035JN015.B02 AL137717 Homo sapiens mRNA; cDNA 2.6E−70  DKFZp434J1630 (from clone DKFZp434J1630) 4098 M00001439D:C09 BC002446 Homo sapiens, MRJ gene for a 0 member of the DNAJ protein family, clone MGC: 1152 IMAGE: 3346070, mRNA, complete cds 17432 I:1965049:16B02:D07 XM_051165 Homo sapiens DKFZP586A0522 0 protein (DKFZP586A0522), mRNA 1785 SL198 XM_051165 Homo sapiens DKFZP586A0522 0 protein (DKFZP586A0522), mRNA 28856 035JN032.E11 X62996 H. sapiens mitochondrial genome 0 (consensus sequence) 18791 RG:229957:10007:D03 D42042 Human mRNA for KIAA0085 gene, 0 partial cds 22950 M00056922C:C09 1882 M00022196B:D09 Z29083 H. sapiens 5T4 gene for 5T4 0 Oncofetal antigen 23886 M00055408A:F10 24995 M00055215C:E11 XM_012880 Homo sapiens hypothetical protein 0 MGC1936 (MGC1936), mRNA 24477 M00055510B:F08 AF240697 Homo sapiens retinol 0 dehydrogenase homolog isoform-2 (RDH) mRNA, complete cds 21681 M00056771C:A12 X02152 Human mRNA for lactate 0 dehydrogenase-A (LDH-A, EC 1.1.1.27) 9557 I:1335140:05A02:C08 X02152 Human mRNA for lactate 0 dehydrogenase-A (LDH-A, EC 1.1.1.27) 22033 M00056574B:A07 873 M00007979C:C05 X00663 Human mRNA fragment for 0 epidermal growth factor (EGF) receptor 17144 RG:25254:10004:D07 M97675 Human transmembrane receptor 0 (ror1) mRNA, complete cds 26970 035JN015.F09 AF097514 Homo sapiens stearoyl-CoA 0 desaturase (SCD) mRNA, complete cds 21402 M00054507C:D07 27074 035Jn031.B03 AF061741 Homo sapiens retinal short-chain 0 dehydrogenase/reductase retSDR1 mRNA, complete cds 10963 I:1258790:05A02:B10 AF072752 Homo sapiens ten integrin EGF- 0 like repeat domains protein precursor (ITGBL1) mRNA, complete cds 29525 035JN026.D12 25514 035JN011.F01 U62961 Human succinyl CoA: 3-oxoacid 0 CoA transferase precursor (OXCT) mRNA, complete cds 26612 035JN016.C08 NM_000240 Homo sapiens monoamine oxidase 0 A (MAOA), nuclear gene encoding mitochondrial protein, mRNA 24600 M00055490C:G11 U57059 Homo sapiens Apo-2 ligand 0 mRNA, complete cds 9741 I:3126828:12A02:G02 U37518 Human TNF-related apoptosis 0 inducing ligand TRAIL mRNA, complete cds 23689 M00054752A:E11 XM_001468 Homo sapiens S100 calcium- 0 binding protein A10 (annexin II ligand, calpactin I, light polypeptide (p11)) (S100A10), mRNA 22352 M00042842B:E02 XM_001468 Homo sapiens S100 calcium- 0 binding protein A10 (annexin II ligand, calpactin I, light polypeptide (p11)) (S100A10), mRNA 23806 RG:2007319:20003:G10 12285 I:1404669:04A01:G12 BC002517 Homo sapiens, Pirin, clone 0 MGC: 2083 IMAGE: 3140037, mRNA, complete cds 27638 035JN011.D10 AK002155 Homo sapiens cDNA FLJ11293 fis, 0 clone PLACE1009670, highly similar to Homo sapiens genethonin 1 mRNA 9663 I:2488567:11A02:H08 XM_006027 Homo sapiens brain-derived 0 neurotrophic factor (BDNF), mRNA 26850 035JN003.B03 XM_031551 Homo sapiens similar to 0 carbohydrate (N- acetylglucosamine-6-O) sulfotransferase 2 (H. sapiens) (LOC90414), mRNA 10204 I:1491445:02B01:F09 AF131765 Homo sapiens clone 24833 0 nonsyndromic hearing impairment protein mRNA sequence, complete cds 1318 2192-6 25922 035JN020.B01 AB020673 Homo sapiens mRNA for 0 KIAA0866 protein, complete cds 26347 035JN025.G02 20361 I:395116:17A02:E05 28672 035JN012.A05 AF126181 Homo sapiens breast cancer- 0 associated gene 1 protein (BCG1) mRNA, complete cds 25520 035JN011.A07 D86956 Human mRNA for KIAA0201 gene, 0 complete cds 1723 M00005694A:A09 BC001980 Homo sapiens, clone 0 IMAGE: 3462291, mRNA 28863 037XN002.A05 25526 035JN011.D07 AF086281 Homo sapiens full length insert 0 cDNA clone ZD45G11 cDNA clone ZD45G11 27936 035JN008.A04 X59445 H. sapiens mRNA for colon 0 carcinoma Manganese Superoxide Dismutase 26851 035JN001.C03 XM_033944 Homo sapiens superoxide 0 dismutase 2, mitochondrial (SOD2), mRNA 25107 M00054825A:E04 AF075061 Homo sapiens full length insert 0 cDNA YP07G10 24912 M00054505D:D06 AF075061 Homo sapiens full length insert 0 cDNA YP07G10 25169 M00055510D:D04 M11167 Human 28S ribosomal RNA gene 1.2E−76  25600 035JN023.A01 BC003107 Homo sapiens, inhibitor of DNA 0 binding 3, dominant negative helix- loop-helix protein, clone MGC: 1988 IMAGE: 3543936, mRNA, complete 28706 035JN016.B05 X55181 Human ETS2 gene, 3′end 0 26377 035JN029.F02 Y14436 Homo sapiens mRNA for 0 phosphatidic acid phosphatase type 2 19460 I:438655:14B02:B04 AF007133 Homo sapiens clone 23764 mRNA 4.5E−113 sequence 25243 RG:1667183:10014: BC000013 Homo sapiens, insulin-like growth 0 F12 factor binding protein 3, clone MGC: 2305 IMAGE: 3506666, mRNA, complete cds 20018 I:1213574:17B01:A11 AB037925 Homo sapiens MAIL mRNA, 3.7E−106 complete cds 918 M00026895D:H03 BC006433 Homo sapiens, Ras-related GTP- 0 binding protein, clone MGC: 13077 IMAGE: 3835186, mRNA, complete cds 25027 RG:1983823:20002:B06 29089 035JN017.B06 XM_037534 Homo sapiens phosphodiesterase 0 7A (PDE7A), mRNA 9141 I:1347384:02A02:C07 U78579 Human type I phosphatidylinositol- 0 4-phosphate 5-kinase beta (STM7) mRNA, partial cds 12005 I:1259230:05A01:C06 D87075 Human mRNA for KIAA0238 gene, 0 partial cds 12148 I:3360476:03B01:B12 XM_040922 Homo sapiens interleukin 13 0 receptor, alpha 2 (IL13RA2), mRNA 17394 RG:1943755:10016:A07 AF346607 Homo sapiens interleukin-1 0 receptor associated kinase 1b (IRAK) mRNA, complete cds, alternatively spliced 27017 035JN021.F03 XM_051742 Homo sapiens spermine synthase 0 (SMS), mRNA 25809 035JN002.B07 XM_009699 Homo sapiens nuclear receptor 0 interacting protein 1 (NRIP1), mRNA 8719 I:2600080:10A01:H01 XM_009665 Homo sapiens Kreisler (mouse) 0 maf-related leucine zipper homolog (KRML), mRNA 21030 RG:1714832:10015:C06 XM_029957 Homo sapiens Rab acceptor 1 0 (prenylated) (RABAC1), mRNA 11436 I:1470085:03B01:F05 XM_038976 Homo sapiens N-ethylmaleimide- 0 sensitive factor attachment protein, alpha (NAPA), mRNA 10374 I:1513989:03B02:C03 XM_009010 Homo sapiens complement 1.4E−96  component 3 (C3), mRNA 19037 I:417827:15A01:G10 X79538 H. sapiens nuk_34 mRNA for 1.9E−28  translation initiation factor 398 M00027016A:C05 XM_031470 Homo sapiens aldolase C,  4E−62 fructose-bisphosphate (ALDOC), mRNA 18773 I:1211682:14A02:C09 XM_008477 Homo sapiens aldolase C, 0 fructose-bisphosphate (ALDOC), mRNA 3583 M00023407B:C10 3418 M00001470A:C03 XM_043951 Homo sapiens CDP-diacylglycerol-- 0 inositol 3-phosphatidyltransferase (phosphatidylinositol syntase) (CDIPT), mRNA 18985 I:1402615:09A02:E03 AF191148 Homo sapiens type I 7.9E−64 transmembrane protein Fn14 mRNA, complete cds 25861 035JN010.D01 XM_047975 Homo sapiens hydroxyacyl 0 glutathione hydrolase (HAGH), mRNA 3317 M00003974D:E04 AF136185 Homo sapiens collagen type XVII 0 (COL17A1) gene; 3′ UTR, long form 8743 I:1858905:04A01:D01 U36775 Human ribonuclease 4 gene, 2.1E−57  partial cds 26240 035JN015.A02 XM_007493 Homo sapiens ribonuclease, 0 RNase A family, 4 (RNASE4), mRNA 28562 037XN007.B11 X00947 Human alpha 1-antichymotrypsin 0 gene fragment 16877 I:2362945:15A01:C07 XM_029378 Homo sapiens checkpoint 1.9E−91  suppressor 1 (CHES1), mRNA 25955 035JN022.C01 AF035620 Homo sapiens BRCA1-associated 0 protein 2 (BRAP2) mRNA, complete cds 26308 035JN023.C02 XM_041470 Homo sapiens zinc finger protein 0 145 (Kruppel-like, expressed in promyelocytic leukemia) (ZNF145), mRNA 4140 2239-4 X03083 Human lactate dehydrogenase-A 0 gene exon 7 and 3′ flanking region 3436 2239-1 X03083 Human lactate dehydrogenase-A 0 gene exon 7 and 3′ flanking region 25612 035JN023.G01 M94856 Human fatty acid binding protein 0 homologue (PA-FABP) mRNA, complete cds 12257 I:1448135:04A01:A06 X15535 H. sapiens lysosomal acid 0 phosphatase gene (EC 3.1.3.2) Exon 11 9111 I:1958902:04A02:D07 D87258 Homo sapiens mRNA for serin 0 protease with IGF-binding motif, complete cds 17620 I:875567:15B01:B08 XM_045326 Homo sapiens MAX-interacting 0 protein 1 (MXI1), mRNA 26025 035JN030.F01 XM_032511 Homo sapiens procollagen-proline, 0 2-oxoglutarate 4-dioxygenase (proline 4-hydroxylase), alpha polypeptide I (P4HA1), mRNA 19271 RG:686684:10010:D04 AF005216 Homo sapiens receptor-associated 0 tyrosine kinase (JAK2) mRNA, complete cds 4151 2035-1 D87953 Human mRNA for RTP, complete 0 cds 26569 035JN010.F02 AB004788 Homo sapiens mRNA for BNIP3L, 0 complete cds 10344 I:2859338:11B02:D03 XM_005052 Homo sapiens angiopoietin 1 1.3E−97  (ANGPT1), mRNA 832 M00021649B:D05 XM_004628 Homo sapiens hypoxia-inducible 0 protein 2 (HIG2), mRNA 12071 I:1798283:06A01:D06 S72481 pantophysin [human, keratinocyte 0 line HaCaT, mRNA, 2106 nt] 12271 I:1445767:04A01:H06 X12701 H. sapiens mRNA for endothelial 1.8E−130 plasminogen activator inhibitor PAI 433 I:1526282:03A01:E05 XM_033627 Homo sapiens glycoprotein 3.7E−117 (transmembrane) nmb (GPNMB), mRNA 20917 RG:222350:10007:C12 X00663 Human mRNA fragment for 1.7E−122 epidermal growth factor (EGF) receptor 25810 035JN004.B07 X00588 Human mRNA for precursor of 0 epidermal growth factor receptor 12039 I:3506985:07A01:D06 M24795 Human CD36 antigen mRNA, 0 complete cds 25499 035JN005.G07 XM_028224 Homo sapiens N- 0 acetylglucosamine-phosphate mutase (AGM1), mRNA 25557 035JN013.D07 BC010135 Homo sapiens, cyclin C, clone 0 IMAGE: 4106819, mRNA 9917 I:1283532:05A01:G09 XM_004148 Homo sapiens 5T4 oncofetal 2.4E−70  trophoblast glycoprotein (5T4), mRNA 19505 RG:204653:10007:A10 XM_003789 Homo sapiens colony stimulating 0 factor 1 receptor, formerly McDonough feline sarcoma viral (v- fms) oncogene homolog (CSF1R), mRNA 17491 RG:277866:10008:B07 XM_003789 Homo sapiens colony stimulating 0 factor 1 receptor, formerly McDonough feline sarcoma viral (v- fms) oncogene homolog (CSF1R), mRNA 10683 I:1686726:06A01:F10 XM_003789 Homo sapiens colony stimulating 0 factor 1 receptor, formerly McDonough feline sarcoma viral (v- fms) oncogene homolog (CSF1R), mRNA 1936 M00008020C:H09 X68277 H. sapiens CL 100 mRNA for 0 protein tyrosine phosphatase 828 M00021638B:F03 X68277 H. sapiens CL 100 mRNA for 0 protein tyrosine phosphatase 9558 I:1824443:05B02:C08 XM_003708 Homo sapiens gamma- 0 aminobutyric acid (GABA) A receptor, pi (GABRP), mRNA 20164 I:1997963:14B02:B05 XM_003631 Homo sapiens solute carrier family 0 25 (mitochondrial carrier; adenine nucleotide translocator), member 4 (SLC25A4), mRNA 969 NIH50_40026 BC008664 Homo sapiens, clone MGC: 9281 0 IMAGE: 3871960, mRNA, complete cds 9910 I:1805840:05B01:C09 XM_003399 Homo sapiens mannosidase, beta 0 A, lysosomal (MANBA), mRNA 2427 M00005767D:B03 XM_047441 Homo sapiens RAP1, GTP-GDP 0 dissociation stimulator 1 (RAP1GDS1), mRNA 19990 RG:1056692:10012:C11 XM_003450 Homo sapiens cyclin G associated 0 kinase (GAK), mRNA 20605 I:690313:16A01:G12 XM_011152 Homo sapiens insulin-like growth 0 factor binding protein 7 (IGFBP7), mRNA 10650 I:2456393:07B01:E10 AK001580 Homo sapiens cDNA FLJ10718 fis, 0 clone NT2RP3001096, weakly similar to Rattus norvegicus leprecan mRNA 25963 035JN022.G01 X53002 Human mRNA for integrin beta-5 0 subunit 25562 035JN015.F07 X53002 Human mRNA for integrin beta-5 0 subunit 9377 I:2782593:12A01:A02 X60656 H. sapiens mRNA for elongation 1.4E−46  factor 1-beta 17618 I:707667:15B01:A08 XM_002273 Homo sapiens inhibitor of DNA 3.5E−117 binding 2, dominant negative helix- loop-helix protein (ID2), mRNA 12136 I:3208994:03B01:D06 U16267 Human AMP deaminase isoform L, 0 alternatively spliced (AMPD2) mRNA, exons 1A, 2 and 3, partial cds 17373 I:1538189:14A02:G07 XM_046818 Homo sapiens similar to receptor 8.3E−123 tyrosine kinase-like orphan receptor 1 (H. sapiens) (LOC92711), mRNA 18577 RG:503209:10010:A09 XM_049305 Homo sapiens Lysosomal- 0 associated multispanning membrane protein-5 (LAPTM5), mRNA 3143 M00001605D:C02 BC003107 Homo sapiens, inhibitor of DNA 1.7E−88  binding 3, dominant negative helix- loop-helix protein, clone MGC: 1988 IMAGE: 3543936, mRNA, complete 17737 RG:155066:10006:E02 AL050147 Homo sapiens mRNA; cDNA 0 DKFZp586E0820 (from clone DKFZp586E0820); partial cds 20029 I:1923613:17A01:G11 AF113123 Homo sapiens carbonyl reductase 0 mRNA, complete cds 18537 NIH50_40304 BC001380 Homo sapiens, succinate 0 dehydrogenase complex, subunit A, flavoprotein (Fp), clone MGC: 1484 IMAGE: 3051442, mRNA, complete cds 10090 NIH50_40304 12102 I:2832414:11B01:C06 XM_048045 Homo sapiens katanin p80 (WD40- 0 containing) subunit B1 (KATNB1), mRNA 8487 I:1375115:05A01:D01 BC001174 Homo sapiens, exostoses 0 (multiple) 1, clone MGC: 2129 IMAGE: 3502232, mRNA, complete cds 9252 I:1673876:06B01:B02 BC000917 Homo sapiens, clone MGC: 5184 0 IMAGE: 3048750, mRNA, complete cds 25605 035JN021.D01 BC000671 Homo sapiens, claudin 4, clone 0 MGC: 1778 IMAGE: 3349211, mRNA, complete cds 29652 M00001610C:D05 BC000588 Homo sapiens, HIRA-interacting 0 protein 3, clone MGC: 1814 IMAGE: 3345739, mRNA, complete cds 10858 I:2458933:04B01:E04 X97544 H. sapiens mRNA for TIM17 8.7E−62  preprotein translocase 1261 M00023419C:B06 U89606 Human pyridoxal kinase mRNA, 0 complete cds 4156 2243-4 X93334 Homo sapiens mitochondrial DNA, 0 complete genome 3452 2243-1 X93334 Homo sapiens mitochondrial DNA, 0 complete genome 2748 2242-6 X93334 Homo sapiens mitochondrial DNA, 0 complete genome 2046 2248-3 X93334 Homo sapiens mitochondrial DNA, 0 complete genome 2044 2242-4 X93334 Homo sapiens mitochondrial DNA, 0 complete genome 1342 2248-2 X93334 Homo sapiens mitochondrial DNA, 0 complete genome 1326 2244-3 X93334 Homo sapiens mitochondrial DNA, 0 complete genome 9981 I:1720149:06A01:G09 AF069604 Homo sapiens myosin light chain 0 kinase isoform 4 (MLCK) mRNA, partial cds 27917 035JN002.H04 XM_015978 Homo sapiens hypothetical protein 1.8E−92  FLJ22969 (FLJ22969), mRNA 8488 I:1808529:05B01:D01 AJ293647 Homo sapiens partial IL4RA gene 1.1E−125 for interleukin-4 receptor alfa chain, exon 11, ECSSQV allele 22793 M00057283C:D06 AF161410 Homo sapiens HSPC292 mRNA, 0 partial cds 26883 035JN005.C03 AF161410 Homo sapiens HSPC292 mRNA, 0 partial cds 11540 I:1909488:10B01:B11 XM_027739 Homo sapiens duodenal 0 cytochrome b (FLJ23462), mRNA 17707 I:489882:14A01:F02 X99474 H. sapiens mRNA for chloride 0 channel, CIC-6c 20649 NIH50_41452 Z14136 H. sapiens gene for 0 spermidine/spermine N1- acetyltransferase 24004 M00056163C:H09 AF107495 Homo sapiens FWP001 and 0 putative FWP002 mRNA, complete cds 11836 I:1806769:01B02:F11 X93036 H. sapiens mRNA for MAT8 protein 0 24932 M00054963C:C09 M26152 Homo sapiens serum amyloid A 0 (SAA) mRNA, complete cds 19143 RG:149960:10006:D04 AK003448 Mus musculus 18 days embryo 8.9E−21  cDNA, RIKEN full-length enriched library, clone: 1110004P15, full insert sequence 26257 035JN013.B08 J04056 Human carbonyl reductase mRNA, 0 complete cds 21239 M00054679B:B03 J02619 Human Z type alpha-1-antitrypsin 0 gene, complete cds (exons 2-5) 16959 I:1426031:14B01:B07 AY035783 Homo sapiens laminin 5 beta 3 3.8E−121 subunit (LAMB3) mRNA, complete cds 2568 M00022158D:C11 XM_036609 Homo sapiens laminin, beta 3 0 (nicein (125 kD), kalinin (140 kD), BM600 (125 kD)) (LAMB3), mRNA 25936 035JN020.A07 XM_036608 Homo sapiens laminin, beta 3 0 (nicein (125 kD), kalinin (140 kD), BM600 (125 kD)) (LAMB3), mRNA 23041 M00054797C:G10 XM_046649 Homo sapiens nuclear factor of 0 kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (NFKBIA), mRNA 9206 I:1822716:05B01:C08 BC008059 Homo sapiens, clone 0 IMAGE: 2967491, mRNA 25105 M00054824C:H04 BC009110 Homo sapiens, clone MGC: 17355 0 IMAGE: 3453825, mRNA, complete cds 24779 M00057061D:G07 22451 M00043372B:B06 X00947 Human alpha 1-antichymotrypsin 0 gene fragment 22291 M00054785D:G05 X00947 Human alpha 1-antichymotrypsin 0 gene fragment 21143 M00055146A:D11 24751 M00054676B:D07 X03083 Human lactate dehydrogenase-A 0 gene exon 7 and 3′ flanking region 24294 M00056163D:E01 X03083 Human lactate dehydrogenase-A 9.4E−110 gene exon 7 and 3′ flanking region 24006 M00056163D:E01 X03083 Human lactate dehydrogenase-A 0 gene exon 7 and 3′ flanking region 25678 035Jn031.H01 AK001670 Homo sapiens cDNA FLJ10808 fis, 4.9E−53  clone NT2RP4000879, weakly similar to UBIQUITIN-ACTIVATING ENZYME E1 22027 M00056534C:E08 XM_003512 Homo sapiens amphiregulin 0 (schwannoma-derived growth factor) (AREG), mRNA 29495 035JN022.E12 D83761 Homo sapiens mRNA for mother 0 against dpp (Mad) related protein, complete cds 24577 M00056654B:G02 XM_038306 Homo sapiens dual specificity 0 phosphatase 6 (DUSP6), mRNA 23527 M00055865C:D04 17090 I:341491:13B01:A01 BC004490 Homo sapiens, v-fos FBJ murine 3.8E−98 osteosarcoma viral oncogene homolog, clone MGC: 11074 IMAGE: 3688670, mRNA, complete cds 25137 M00057167A:C07 23772 M00056360A:E07 BC004490 Homo sapiens, v-fos FBJ murine 0 osteosarcoma viral oncogene homolog, clone MGC: 11074 IMAGE: 3688670, mRNA, complete cds 1659 M00001350B:D10 BC004490 Homo sapiens, v-fos FBJ murine 0 osteosarcoma viral oncogene homolog, clone MGC: 11074 IMAGE: 3688670, mRNA, complete cds 8497 I:2170638:05A01:A07 BC006169 Homo sapiens, Similar to SH3- 5.2E−125 domain binding protein 5 (BTK- associated), clone MGC: 13234 IMAGE: 4025362, mRNA, complete cds 25272 M00054621A:D09 AF161435 Homo sapiens HSPC317 mRNA, 0 partial cds 21216 M00056194B:G06 XM_002844 Homo sapiens procollagen-lysine, 0 2-oxoglutarate 5-dioxygenase (lysine hydroxylase) 2 (PLOD2), mRNA 11939 I:2938757:02A02:B05 D43767 Human mRNA for chemokine, 0 complete cds 9191 I:1421929:05A01:D02 X63629 H. sapiens mRNA for p cadherin 2.4E−90  3429 2024-3 AF002697 Homo sapiens E1B 19K/Bcl-2- 0 binding protein Nip3 mRNA, nuclear gene encoding mitochondrial protein, complete cds 2725 2024-1 AF002697 Homo sapiens E1B 19K/Bcl-2- 0 binding protein Nip3 mRNA, nuclear gene encoding mitochondrial protein, complete cds 19923 I:1001356:13A01:B11 BC006318 Homo sapiens, erythrocyte 1.7E−103 membrane protein band 4.9 (dematin), clone MGC: 12740 IMAGE: 4125804, mRNA, complete cds 20457 I:1923289:19A01:E06 XM_035603 Homo sapiens gap junction protein, 0 beta 5 (connexin 31.1) (GJB5), mRNA 24773 M00057055D:B11 24119 M00042886D:H10 BC006260 Homo sapiens, Similar to N-myc 4.4E−114 downstream regulated, clone MGC: 11293 IMAGE: 3946764, mRNA, complete cds 3908 M00027080A:E06 M60756 Human histone H2B.1 mRNA, 3′ 0 end 8560 I:2346704:06B01:H01 AJ000334 Homo sapiens mRNA for cytosolic 0 asparaginyl-tRNA synthetase 24588 M00055411A:C10 L19779 Homo sapiens histone H2A.2 0 mRNA, complete cds 4047 M00007997C:B08 XM_009091 Homo sapiens glycogen synthase 0 1 (muscle) (GYS1), mRNA 28344 035JN011.E11 XM_050471 Homo sapiens glycogen synthase 0 1 (muscle) (GYS1), mRNA 27561 035JN001.F04 XM_001472 Homo sapiens v-jun avian sarcoma 0 virus 17 oncogene homolog (JUN), mRNA 3272 M00022165C:E12 NM_001024 Homo sapiens ribosomal protein 0 S21 (RPS21), mRNA 26735 035JN030.A08 XM_010408 Homo sapiens RAB9-like protein 0 (RAB9L), mRNA 24900 M00054500D:C08 BC004427 Homo sapiens, proteasome 0 (prosome, macropain) subunit, alpha type, 7, clone MGC: 3755 IMAGE: 2819923, mRNA, complete cds 9472 I:2510171:04B01:H08 X04503 Human SLPI mRNA fragment for 0 secretory leucocyte protease inhibitor 9979 I:1623318:06A01:F09 L31409 Homo sapiens creatine transporter 2.2E−45  mRNA, complete cds 21996 M00042467B:B04 L00160 Human phosphoglycerate kinase 0 (pgk) mRNA, exons 2 to last 22312 M00055035D:F05 11327 I:3139773:05A01:H11 L00160 Human phosphoglycerate kinase 2.6E−21  (pgk) mRNA, exons 2 to last 18240 RG:1927470:10015:H08 V00572 Human mRNA encoding 0 phosphoglycerate kinase 21922 M00054848A:D12 AF139065 Homo sapiens desmoplakin I 0 mRNA, partial cds 22290 M00057002D:H01 10390 I:1405391:03B02:C09 AF056979 Homo sapiens clone YAN1 0 interferon-gamma receptor mRNA, complete cds 2212 M00008098B:F06 U19247 Homo sapiens interferon-gamma 0 receptor alpha chain gene, exon 7 and complete cds 20213 RG:221172:10007:C11 S74774 p59fyn(T) = OKT3-induced calcium 2.9E−103 influx regulator [human, Jurkat J6 T cell line, mRNA Partial, 1605 nt] 24955 M00055929D:D04 19574 I:635178:13B02:C10 XM_033944 Homo sapiens superoxide 0 dismutase 2, mitochondrial (SOD2), mRNA 19969 RG:501476:10010:A05 U14394 Human tissue inhibitor of 0 metalloproteinases-3 mRNA, complete cds 8570 I:1696224:06B01:E07 X70684 C. aethiops mRNA for heat shock 5.6E−25  protein 70 18519 I:1997703:13A01:D09 X52947 Human mRNA for cardiac gap 0 junction protein 9616 I:3200341:06B02:H02 Y00106 Human gene for beta-adrenergic 0 receptor (beta-2 subtype) 22334 M00055067D:H12 17459 I:2056395:13A02:B07 M77349 Human transforming growth factor- 2.5E−121 beta induced gene product (BIGH3) mRNA, complete cds 25193 M00056763B:A12 X68277 H. sapiens CL 100 mRNA for 0 protein tyrosine phosphatase 25191 M00056763B:A12 X68277 H. sapiens CL 100 mRNA for 0 protein tyrosine phosphatase 9448 I:2455617:04B01:D02 XM_051799 Homo sapiens guanosine 0 monophosphate reductase (GMPR), mRNA 25224 RG:950682:10003:D06 BC002536 Homo sapiens, 0 phosphofructokinase, platelet, clone MGC: 2192 IMAGE: 3140233, mRNA, complete cds 20218 RG:2158297:10016:E11 BC002536 Homo sapiens, 0 phosphofructokinase, platelet, clone MGC: 2192 IMAGE: 3140233, mRNA, complete cds 3089 NIH50_26184 D25328 Human mRNA for platelet-type   2E−108 phosphofructokinase, complete cds 23985 NIH50_26184 19953 NIH50_26184 D25328 Human mRNA for platelet-type   2E−108 phosphofructokinase, complete cds 11506 NIH50_26184 22362 M00056349A:F08 M10546 Human mitochondrial DNA, 1.2E−86  fragment M1, encoding transfer RNAs, cytochrome oxidase I, and 2 URFs 25516 035JN011.G01 XM_011470 Homo sapiens myristoylated 0 alanine-rich protein kinase C substrate (MARCKS, 80K-L) (MACS), mRNA 25757 037XN005.H07 AF017116 Homo sapiens type-2 phosphatidic 0 acid phosphohydrolase (PAP2) mRNA, complete cds 24814 M00042773B:E09 M17733 Human thymosin beta-4 mRNA, 0 complete cds 21994 M00042465B:E04 M17733 Human thymosin beta-4 mRNA, 0 complete cds 27117 037XN001.H03 BC001631 Homo sapiens, prothymosin beta 4, 0 clone MGC: 2219 IMAGE: 3536637, mRNA, complete cds 24681 NIH50_41452 22745 M00056592A:B08 NM_003739 Homo sapiens aldo-keto reductase 0 family 1, member C3 (3-alpha hydroxysteroid dehydrogenase, type II) (AKR1C3), mRNA 24233 M00055873C:B06 2001 M00001381A:F03 XM_035387 Homo sapiens ribosomal protein, 0 large, P1 (RPLP1), mRNA 21179 NIH50_43550 17147 NIH50_43550 AK026515 Homo sapiens cDNA: FLJ22862 0 fis, clone KAT01966, highly similar to HSLDHAR Human mRNA for lactate dehydrogenase-A 8700 NIH50_43550 21214 M00056193B:D06 BC006260 Homo sapiens, Similar to N-myc 0 downstream regulated, clone MGC: 11293 IMAGE: 3946764, mRNA, complete cds 26422 037XN003.D08 BC006260 Homo sapiens, Similar to N-myc 0 downstream regulated, clone MGC: 11293 IMAGE: 3946764, mRNA, complete cds 22837 M00055891C:B09 21965 M00057029A:G09 25541 035JN013.D01 AK026310 Homo sapiens cDNA: FLJ22657 0 fis, clone HSI07791, highly similar to HUMCYB5 Human cytochrome b5 mRNA 18302 I:1738248:09B02:G08 XM_016114 Homo sapiens hypothetical protein 0 FLJ22501 (FLJ22501), mRNA 24049 M00054706B:G04 AF107495 Homo sapiens FWP001 and 0 putative FWP002 mRNA, complete cds 26326 035JN023.D08 AK025906 Homo sapiens cDNA: FLJ22253 0 fis, clone HRC02763 2254 M00004085C:C02 AK025703 Homo sapiens cDNA: FLJ22050 0 fis, clone HEP09454 10296 I:2868216:07B02:D09 AK025703 Homo sapiens cDNA: FLJ22050 0 fis, clone HEP09454 20044 I:2547084:09B01:F05 XM_016847 Homo sapiens hypothetical protein 0 FLJ22002 (FLJ22002), mRNA 28806 035JN028.D05 AK025504 Homo sapiens cDNA: FLJ21851 0 fis, clone HEP01962 17566 I:446969:17B02:G07 AK023217 Homo sapiens cDNA FLJ13155 fis,   2E−115 clone NT2RP3003433 19005 I:2674167:09A02:G09 AK022968 Homo sapiens cDNA FLJ12906 fis, 0 clone NT2RP2004373 3567 M00023369D:C05 21983 M00057081B:H03 458 M00022134B:E08 XM_037412 Homo sapiens hypothetical gene 0 supported by BC008993 (LOC91283), mRNA 22331 M00057138A:E11 21411 M00055833D:B03 22972 M00056956D:B01 24533 RG:1643392:10014:C11 24853 M00056617D:F07 AK020869 Mus musculus adult retina cDNA, 6.5E−59  RIKEN full-length enriched library, clone: A930017A02, full insert sequence 23753 M00054915A:G02 21502 M00056193B:D06 18180 RG:39422:10005:B02 23918 M00056278C:E03 24144 RG:1982961:20001:H05 19996 RG:1283072:10012:F11 BC009107 Homo sapiens, clone MGC: 17352 0 IMAGE: 3449913, mRNA, complete cds 11528 I:1899534:10B01:D05 20506 I:1969044:18B01:E12 AB048286 Homo sapiens GS1999full mRNA, 0 complete cds 23833 RG:1656861:10014:E10 20042 I:1873176:09B01:E05 BC001909 Homo sapiens, clone 0 IMAGE: 3537447, mRNA, partial cds 24977 M00055820D:F01 11646 I:1723142:08B02:G11 AK014612 Mus musculus 0 day neonate skin 4.6E−45  cDNA, RIKEN full-length enriched library, clone: 4633401I05, full insert sequence 24872 RG:773612:10011:D06 10577 I:2174196:08A01:A10 21710 RG:1091554:10003:G01 18556 RG:31082:10004:F09 29433 035JN014.F12 AK001805 Homo sapiens cDNA FLJ10943 fis, 0 clone OVARC1001360 29273 037XN005.F12 28763 035JN018.G11 AJ310543 Homo sapiens mRNA for EGLN1 1.9E−40  protein 27887 RG:2364147:8119908:A10 27450 035JN032.F09 27255 035JN006.E09 XM_027456 Homo sapiens hypothetical gene 1.2E−57  supported by AK000584 (LOC89942), mRNA 27226 035JN004.F09 26550 035JN008.D08 26508 035JN004.G02 26483 RG:2377371:8119908:C08 26334 035JN023.H08 AF364547 Homo sapiens methylmalonyl-CoA 0 epimerase mRNA, complete cds; nuclear gene for mitochondrial product 26027 035JN030.G01 25977 035JN022.F07 25965 035JN022.H01 25844 035JN008.C07 25834 035JN008.F01 AB048289 Bos taurus lae mRNA for lipoate- 3.1E−35  activating enzyme, complete cds 25816 035JN004.E07 25746 037XN007.B07 25742 037XN007.H01 25741 037XN005.H01 25712 037XN003.A07 25642 035Jn027.F01 25621 035JN021.D07 AK027321 Homo sapiens cDNA FLJ14415 fis, 0 clone HEMBA1004889, weakly similar to Human C3f mRNA 25614 035JN023.H01 25603 035JN021.C01 25556 035JN015.C07 25555 035JN013.C07 25540 035JN015.C01 23576 RG:1984769:20002:D10 22566 RG:1996656:20003:C03 9036 DD182 4164 M00007932B:E06 4146 2179-5 4091 M00026845A:E01 4072 M00023398A:G12 4022 M00022127D:B06 3965 M00005406A:f04 3954 M00005400B:E1 3872 M00007974D:B04 3869 M00003868C:A03 3838 M00007052A:C09 XM_048272 Homo sapiens similar to Ras- 0 related GTP-binding protein (H. sapiens) (LOC92951), mRNA 3806 2168-2 3798 2138-4 3792 2171-5 3788 2156-4 3767 M00001355D:H12 3458 M00007160D:E10 3251 M00005471A:a04 3194 DF821 3102 2167-1 3094 2138-3 2671 M00023431A:D02 2634 M00008025D:A04 2567 M00008061B:A12 2317 M00001502D:E09 1958 M00023296B:B09 1680 2169-5 1625 M00001542C:G08 1445 M00023335C:C09 1320 2207-5 974 2161-1 726 DO15 718 ER418 703 M00004189D:A11 652 M00007070A:C08 630 2203-2 593 M00001373A:A06 X93036 H. sapiens mRNA for MAT8 protein 0 532 M00022005A:H05 272 2168-5 256 M00001406C:H12 57 M00023371B:H02

TABLE 18 3D T4-2/ SEQ ID SPOT 2D T4-2/ 3D T4-2/ 3D S1/ 3D T4-2/ 3D T4-2/ B1 Integrin 3D T4-2/ NO. ID 2D S1 3D S1 2D S1 2D T4-2 EGFR Ab Ab Tyr 2506 10594 0.6 2.2 0.6 1.9 3.0 1.0 2.9 2507 21851 1.0 1.0 1.0 3.5 1.3 1.0 1.0 2508 20990 1.6 4.6 1.0 1.5 1.0 1.0 1.0 2509 18641 1.0 0.6 2.6 1.7 1.0 1.6 1.0 2510 17229 0.3 0.8 1.0 2.1 1.0 1.0 1.0 2511 25930 1.0 1.0 1.0 1.0 1.0 1.0 1.0 2512 20701 1.6 2.9 1.3 2.7 4.5 1.9 5.8 2513 20346 1.7 2.7 1.4 2.6 4.3 2.0 5.2 2514 21247 1.0 4.4 1.5 3.0 3.4 2.6 4.7 2515 23062 0.6 2.5 0.6 1.8 3.3 1.4 2.7 2516 25666 1.0 2.9 0.6 2.0 3.6 1.0 2.3 2517 19001 8.5 14.2 1.0 1.0 4.8 1.7 8.0 2518 10897 1.0 3.1 4.5 1000.0 13.3 4.6 18.4 2519 1960 0.3 1.5 3.0 13.7 3.9 2.4 4.9 2520 26381 1.0 1.0 1.0 0.9 1.0 1.0 1.0 2521 26719 0.4 1.0 0.6 2.8 1.2 1.7 1.0 2522 27152 4.2 3.0 2.2 1.5 1.3 1.0 1.3 2523 10926 0.7 1.9 0.9 2.1 3.7 1.5 3.3 2524 28980 0.6 1.4 1.0 2.4 1.0 1.0 1.0 2525 1236 1.0 2.8 0.8 2.1 2.2 1.8 3.2 2526 29350 0.5 0.6 1.2 2.1 1.4 1.0 1.0 2527 26242 1.0 1.0 0.6 2.2 1.0 1.0 2.0 2528 4098 1.4 3.9 0.6 2.1 2.7 1.3 3.1 2529 17432 0.4 0.3 2.4 2.1 0.3 0.9 0.3 2530 1785 0.5 0.4 2.4 2.0 0.3 1.0 0.3 2531 28856 8.5 0.9 2.5 0.3 0.6 1.0 0.5 2532 18791 1.0 0.2 0.3 4.1 1.0 1.0 1.3 2533 22950 3.9 4.1 1.2 1.0 2.1 1.0 2.4 2534 1882 2.4 4.1 0.9 1.8 3.2 1.5 4.7 2535 23886 1.0 1.0 1.2 2.1 1.0 1.0 1.0 2536 24995 2.0 1.6 2.1 1.0 1.0 1.0 1.0 2537 24477 1.0 1.9 1.0 4.2 2.7 1.3 1.8 2538 21681 1.7 7.1 0.6 2.0 2.8 1.0 3.6 2539 9557 1.6 7.5 0.8 1.0 3.0 1.0 2.5 2540 22033 2.8 3.7 1.0 0.9 2.2 1.0 2.7 2541 873 1.0 4.0 1.0 2.7 1.7 1.0 1.0 2542 17144 1.0 0.5 3.6 1.4 1.0 1.0 1.0 2543 26970 6.0 15.3 0.2 0.6 2.9 1.0 5.4 2544 21402 0.2 1.0 2.8 6.9 2.4 1.0 3.6 2545 27074 1.7 2.5 2.3 3.2 1.6 1.0 2.0 2546 10963 0.5 0.3 2.1 0.5 1.0 1.0 0.7 2547 29525 0.6 1.0 0.7 2.4 1.7 1.3 1.0 2548 25514 1000.0 1.0 1.0 1.0 0.5 1.0 1.0 2549 26612 0.4 0.5 1.6 2.8 0.8 1.0 0.8 2550 24600 1.6 2.7 1.0 2.0 1.0 1.2 1.4 2551 9741 2.3 5.0 1.0 2.2 1.7 1.0 1.0 2552 23689 1.0 2.6 0.8 1.8 2.3 1.0 2.7 2553 22352 1.0 2.9 0.7 1.6 2.4 1.0 2.4 2554 23806 1.0 0.4 1.3 2.3 1.0 1.4 1.4 2555 12285 1.0 1.0 1.0 1.0 0.8 1.0 0.5 2556 27638 0.6 1.0 0.8 2.2 2.1 1.0 1.0 2557 9663 1.0 1.0 1.0 1000.0 1.0 1.0 1.0 2558 26850 1.0 0.2 9.1 2.1 1.3 1.6 2.2 2559 10204 2.9 2.3 0.8 0.6 3.1 1.4 2.4 2560 1318 2.0 0.9 2.3 0.5 0.6 1.1 0.7 2561 25922 1.0 0.8 1.0 1.0 1.0 1.0 1.0 2562 26347 1.0 1.0 1.0 1.0 1.0 1.0 1.0 2563 20361 1.0 1.0 1.0 2.0 1.0 1.0 1.0 2564 28672 0.6 2.1 0.6 2.1 1.4 1.0 1.7 2565 25520 0.5 0.3 2.3 1.3 1.0 0.7 0.5 2566 1723 1.0 0.5 5.1 3.5 1.0 3.1 1.0 2567 28863 0.8 1.3 1.0 2.3 1.7 1.7 1.7 2568 25526 5.9 1.7 1.0 0.6 0.6 0.7 0.4 2569 27936 1.0 1.0 3.2 3.1 1.9 3.1 1.5 2570 26851 1.0 0.7 3.2 2.7 1.6 2.4 1.3 2571 25107 1.0 5.8 1.0 2.6 2.6 1.6 2.6 2572 24912 1.0 2.9 1.0 2.4 1.6 1.3 1.8 2573 25169 1.0 0.7 2.5 1.5 1.0 1.0 1.0 2574 25600 1.6 1.4 2.9 2.1 0.7 0.9 0.5 2575 28706 0.2 0.5 0.6 2.1 1.3 1.2 1.0 2576 26377 0.6 0.3 2.2 1.0 1.2 1.3 1.0 2577 19460 2.4 1.5 2.5 1.3 1.0 1.0 0.8 2578 25243 1.0 0.7 2.2 1.0 1.0 1.0 1.0 2579 20018 1.0 1.0 1.0 2.6 1.0 1.0 1.0 2580 918 1.0 1.7 1.3 2.1 2.0 1.6 2.4 2581 25027 1.0 1.0 1.0 1.0 1.0 1.0 1.0 2582 29089 0.6 0.5 0.8 2.1 1.0 1.0 1.0 2583 9141 1.0 1.0 1.0 1.0 1.0 1.0 1.0 2584 12005 1.0 1.0 2.2 1.0 1.0 1.0 1.0 2585 12148 1.0 1.0 1.0 1.0 1.0 1.0 1.0 2586 17394 0.4 0.6 2.1 2.0 1.0 1.0 1.0 2587 27017 2.8 3.3 0.8 1.0 2.4 1.8 2.8 2588 25809 1.0 1.0 1000.0 1.0 1.0 1.0 1.0 2589 8719 0.1 1.0 2.3 2.1 0.4 0.5 0.3 2590 21030 0.4 1.0 1.3 2.1 1.4 1.6 1.4 2591 11436 0.7 0.4 2.0 1.0 0.6 0.8 0.6 2592 10374 1.5 1.5 3.5 2.7 0.4 1.0 0.3 2593 19037 3.0 3.3 0.9 1.5 2.7 1.4 3.7 2594 398 1.6 6.9 1.1 3.3 2.4 1.0 4.5 2595 18773 1.9 5.1 1.0 3.9 3.8 2.0 6.1 2596 3583 0.5 0.7 1.0 2.0 2.5 1.0 1.5 2597 3418 1.8 3.2 1.2 2.4 1.6 1.0 1.2 2598 18985 9.2 3.1 1.0 0.6 2.3 1.1 2.5 2599 25861 3.4 1.5 2.0 0.8 0.8 0.9 0.6 2600 3317 0.9 2.3 1.0 3.4 1.9 1.0 1.0 2601 8743 0.2 0.7 1.0 4.3 1.8 1.0 1.7 2602 26240 0.2 1.0 1.0 5.3 1.9 1.9 1.1 2603 28562 0.3 0.2 2.0 1.0 0.5 0.5 0.6 2604 16877 1.0 2.6 1.1 2.6 1.7 1.5 1.3 2605 25955 1.0 1.0 1.0 1.0 1.0 1.0 1.0 2606 26308 0.2 0.4 1.0 2.2 0.7 0.8 0.6 2607 4140 1.9 6.7 0.7 2.1 3.0 1.0 3.5 2608 3436 1.8 6.3 0.6 2.2 3.1 1.3 3.3 2609 25612 1.0 12.5 1.0 1.0 2.1 1.0 2.9 2610 12257 1.0 1.0 2.0 1.0 0.8 0.9 0.8 2611 9111 0.5 0.5 2.2 1.3 1.5 1.0 0.7 2612 17620 0.3 0.8 1.0 3.2 2.7 2.1 1.0 2613 26025 1.0 2.9 1.1 2.2 2.3 1.0 2.6 2614 19271 0.5 1.3 0.7 2.2 1.6 1.2 1.5 2615 4151 0.4 4.2 1.2 11.1 4.2 1.0 2.9 2616 26569 0.7 2.2 0.8 2.9 2.3 1.7 2.6 2617 10344 1.0 1.0 1.0 1.0 1.0 1.0 1.0 2618 832 1.0 3.3 1.0 2.4 3.7 2.2 4.0 2619 12071 1.8 1.5 2.2 1.0 1.3 0.8 1.4 2620 12271 0.6 4.9 1.9 14.9 20.8 4.0 24.1 2621 11433 0.5 0.4 5.7 3.0 1.7 1.8 1.0 2622 20917 1.0 2.8 0.9 2.6 1.7 1.4 1.7 2623 25810 1.1 3.8 1.0 2.9 1.5 1.3 1.5 2624 12039 1.0 1.0 3.6 1.0 1.0 1.0 1.0 2625 25499 1.0 1.0 1.0 1.0 1.0 1.0 1.0 2626 25557 1.0 1.8 1.0 0.8 1.0 1.0 1.0 2627 9917 2.5 2.7 0.7 1.6 3.8 1.2 3.6 2628 19505 0.4 1.7 0.7 3.8 1.7 1.6 1.4 2629 17491 0.6 1.7 0.7 2.5 1.6 1.3 1.4 2630 10683 0.4 1.9 0.6 3.6 1.7 1.4 1.1 2631 1936 0.2 0.6 0.6 3.1 1.0 1.8 1.0 2632 828 0.1 1.0 0.5 3.0 1.0 1.7 1.2 2633 9558 1.0 1.0 1.0 1.0 1.0 1.0 1.0 2634 20164 2.0 1.1 2.5 1.7 1.0 1.0 0.8 2635 969 1.0 1.0 2.7 1.0 1.0 1.5 0.7 2636 9910 0.4 1.0 0.8 3.2 1.9 1.3 1.4 2637 2427 1.3 0.7 3.0 2.8 0.8 1.9 1.0 2638 19990 1.0 7.9 2.8 34.7 1.0 1.0 1.0 2639 20605 3.0 1.2 2.1 1.0 1.3 1.2 0.8 2640 10650 0.5 1.7 0.5 2.9 2.8 0.6 3.4 2641 25963 2.6 3.5 0.7 1.0 3.3 1.0 2.3 2642 25562 3.2 5.9 0.7 1.0 4.2 1.0 4.8 2643 9377 0.6 1.0 1.0 2.1 1.9 2.0 1.6 2644 17618 1.0 0.7 2.3 3.2 0.8 0.7 0.8 2645 12136 1.0 1.0 3.8 1.0 1.0 1.0 1.0 2646 17373 1.0 0.4 6.1 2.4 1.0 1.0 1.0 2647 18577 1.0 0.3 0.3 4.6 1.0 1.0 1.0 2648 3143 1.7 1.3 2.6 2.3 0.7 1.0 0.5 2649 17737 6.1 0.7 3.4 0.3 0.5 1.3 0.4 2650 20029 1.0 0.6 2.3 1.0 1.0 1.0 0.5 2651 18537 1.0 1.3 2.1 2.6 1.3 1.0 1.2 2652 10090 1.0 1.7 2.1 2.8 1.5 1.0 1.2 2653 12102 1.0 1.0 3.9 1.0 1.0 1.0 1.0 2654 8487 4.7 2.4 1.0 1.0 2.3 1.1 2.2 2655 9252 1.3 3.8 0.3 1.0 2.1 1.6 2.5 2656 25605 1.0 1.0 1.0 1.0 0.5 0.5 1.0 2657 29652 1.0 2.9 1.5 2.9 2.0 1.5 2.1 2658 10858 1.0 0.8 2.0 1.0 1.0 1.0 0.7 2659 1261 0.2 0.6 1.0 2.9 0.8 0.8 0.9 2660 4156 12.4 0.8 3.1 0.2 0.6 1.0 0.3 2661 3452 10.6 0.8 2.8 0.3 0.6 1.0 0.4 2662 2748 10.8 0.8 3.1 0.2 0.5 1.0 0.4 2663 2046 9.2 1.0 2.4 0.3 0.5 1.2 0.4 2664 2044 11.7 0.8 2.8 0.2 0.6 1.4 0.4 2665 1342 10.5 0.9 2.8 0.2 0.5 1.2 0.4 2666 1326 12.2 1.0 2.7 0.2 0.5 1.0 0.4 2667 9981 0.2 1.5 0.3 2.5 1.2 1.6 0.5 2668 27917 1.9 2.5 0.5 1.0 2.1 1.4 2.3 2669 8488 4.3 2.4 1.0 0.5 2.9 0.9 3.6 2670 22793 1.9 2.6 0.5 1.0 2.2 1.8 2.1 2671 26883 2.4 3.7 0.5 1.0 2.5 2.0 2.0 2672 11540 0.7 1.0 1.3 2.8 0.8 1.0 0.5 2673 17707 1.0 0.6 2.6 1.0 1.0 1.0 1.0 2674 20649 2.3 2.6 0.5 0.4 3.0 1.0 3.1 2675 24004 1.0 2.5 1.8 3.6 2.3 1.0 2.8 2676 11836 1.2 5.0 0.9 3.7 1.3 1.0 0.8 2677 24932 1.8 0.8 6.5 2.1 0.8 1.0 0.5 2678 19143 0.6 1.6 0.7 2.0 1.7 1.2 1.4 2679 26257 1.9 1.3 2.2 1.7 0.7 1.0 0.6 2680 21239 9.4 9.2 0.5 0.4 2.4 1.0 2.7 2681 16959 0.6 2.1 0.8 2.1 3.0 1.4 2.5 2682 2568 0.7 1.9 0.7 2.2 3.0 1.3 2.4 2683 25936 1.0 2.4 0.7 2.0 3.1 1.5 2.4 2684 23041 0.7 1.0 2.1 2.6 1.0 1.4 1.0 2685 9206 5.7 1.8 4.6 1.0 1.0 0.7 0.9 2686 25105 1.6 1.3 2.1 1.0 1.0 0.7 0.8 2687 24779 1.0 1.0 1.0 2.9 2.3 1.4 1.2 2688 22451 1.0 0.2 2.1 1.0 1.4 0.6 1.0 2689 22291 0.2 0.2 2.1 1.0 0.6 0.6 0.5 2690 21143 1.0 7.2 0.7 2.0 2.6 1.1 2.4 2691 24751 1.7 5.0 0.7 2.1 2.4 1.3 4.0 2692 24294 1.7 3.9 0.8 2.4 2.6 1.1 3.9 2693 24006 1.7 6.3 0.8 2.5 2.4 1.0 4.0 2694 25678 1.0 1.0 1.0 1.0 1.0 1.0 1.0 2695 22027 8.7 7.0 0.4 0.2 5.1 2.0 5.2 2696 29495 1.0 1.0 1.0 1.0 1.0 1.0 1.0 2697 24577 6.8 3.2 0.8 0.4 3.8 1.3 2.1 2698 23527 0.3 2.1 1.6 6.4 2.7 2.1 3.4 2699 17090 1.0 4.9 0.7 2.3 3.1 2.3 3.6 2700 25137 1.0 1.0 0.4 3.8 1.0 2.5 4.1 2701 23772 0.6 6.8 0.5 3.7 12.6 3.6 9.2 2702 1659 1.0 7.5 0.3 3.2 17.8 4.1 20.3 2703 8497 1.3 0.4 2.2 0.5 1.0 1.0 1.0 2704 25272 8.0 6.0 1.0 0.6 2.2 1.0 2.9 2705 21216 1.0 1.0 0.6 2.0 2.5 2.0 2.2 2706 11939 1.0 1.0 1.0 1.0 1.0 1.0 1.0 2707 9191 1.8 2.2 1.3 1.1 2.2 1.0 2.0 2708 3429 0.7 3.4 0.8 3.5 3.0 1.5 3.7 2709 2725 0.8 3.4 1.0 3.4 2.6 1.6 4.1 2710 19923 1.0 1.1 2.9 1.0 1.7 1.4 1.2 2711 20457 1.0 2.0 1.0 2.3 2.9 1.0 2.3 2712 24773 0.2 1.0 0.8 2.0 1.6 1.0 1.0 2713 24119 0.2 4.6 1.1 15.9 2.7 1.0 3.4 2714 3908 0.3 0.5 1.1 2.3 1.7 1.0 1.0 2715 8560 1.9 0.7 2.2 0.5 1.0 1.0 0.7 2716 24588 0.3 0.5 1.0 2.0 1.0 1.0 1.4 2717 4047 0.5 1.2 1.0 2.1 1.9 1.0 1.8 2718 28344 0.8 1.0 1.0 2.0 1.7 1.5 2.7 2719 27561 1.0 1.0 1.0 2.4 1.2 1.2 1.3 2720 3272 0.6 0.8 1.0 2.1 1.3 1.6 1.0 2721 26735 1.0 1.0 1.0 1.0 1.0 1.0 1.0 2722 24900 0.3 0.8 2.9 5.7 2.2 1.1 3.0 2723 9472 2.2 5.0 1.0 2.0 1.5 0.8 1.7 2724 9979 1.3 3.3 1.5 3.9 3.4 1.4 2.5 2725 21996 1.0 4.7 1.0 3.4 2.5 1.0 2.4 2726 22312 1.2 4.4 1.2 3.3 2.2 1.1 2.2 2727 11327 1.4 6.2 1.4 2.7 2.7 1.0 2.2 2728 18240 2.0 4.5 1.0 2.2 2.1 1.0 2.7 2729 21922 0.7 1.4 0.8 2.1 1.8 1.0 1.3 2730 22290 0.7 1.6 0.9 2.1 1.5 1.2 1.3 2731 10390 1.3 1.0 2.6 1.6 0.8 1.0 0.6 2732 2212 1.9 1.0 2.8 1.0 0.6 1.6 0.8 2733 20213 0.4 1.0 1.0 1.0 1.0 1.0 1.0 2734 24955 0.9 2.9 1.0 3.3 0.8 0.8 1.0 2735 19574 1.0 0.6 3.7 3.1 1.5 2.6 1.4 2736 19969 1.0 1.0 1.0 3.1 1.0 1.0 1.0 2737 8570 0.4 1.2 1.0 2.6 1.2 0.8 0.6 2738 18519 3.5 2.9 2.6 1.8 1.8 1.0 2.0 2739 9616 0.6 2.0 1.0 2.3 1.2 1.2 1.0 2740 22334 0.2 0.7 2.9 8.5 1.7 1.1 3.4 2741 17459 0.1 0.7 2.7 18.8 4.0 1.3 4.6 2742 25193 1.0 0.8 1.0 2.3 1.0 1.3 1.0 2743 25191 0.2 0.8 0.7 2.5 1.3 1.5 1.2 2744 9448 0.6 1.0 1.0 2.3 0.8 0.8 0.5 2745 25224 5.6 14.4 1.0 2.3 6.0 1.5 9.6 2746 20218 6.1 12.3 0.7 1.7 5.6 1.6 9.0 2747 3089 7.0 15.7 0.7 2.3 7.3 1.8 8.0 2748 23985 5.8 17.2 0.9 2.1 6.8 1.8 8.1 2749 19953 6.2 13.5 0.8 1.8 6.4 1.7 10.4 2750 11506 4.1 13.3 1.0 1.4 4.4 1.6 7.2 2751 22362 1.0 0.7 4.1 2.1 1.2 1.8 1.0 2752 25516 0.7 10.1 0.4 4.0 14.7 4.7 8.1 2753 25757 0.6 0.4 2.4 1.0 1.0 1.3 0.9 2754 24814 0.5 2.8 0.3 1.0 3.5 1.4 4.4 2755 21994 0.5 3.2 0.3 1.0 3.6 1.0 4.3 2756 27117 1.0 2.8 0.3 1.0 3.9 1.0 4.9 2757 24681 1.8 2.6 0.6 0.5 3.2 1.5 3.0 2758 22745 0.3 2.4 1.4 8.1 2.8 2.3 3.5 2759 24233 1.9 3.9 1.3 2.3 1.3 0.8 2.2 2760 2001 1.0 1.0 1.5 2.1 1.0 1.0 1.0 2761 21179 2.0 7.9 0.7 1.9 2.1 1.0 4.3 2762 17147 1.3 4.3 0.7 1.7 2.4 1.2 3.9 2763 8700 1.5 7.3 0.7 1.6 3.1 1.0 2.7 2764 21214 0.3 5.4 1.2 15.5 3.1 1.0 3.6 2765 26422 0.4 3.7 1.0 12.7 3.9 1.0 3.3 2766 22837 0.7 1.0 2.1 2.4 1.2 1.5 0.9 2767 21965 1.0 1.0 1.0 2.2 2.4 1.0 1.0 2768 25541 4.5 2.7 2.7 0.8 1.0 1.3 0.8 2769 18302 1.1 0.9 2.1 1.0 1.0 1.0 1.0 2770 24049 1.0 2.6 1.5 2.5 2.3 1.4 2.4 2771 26326 9.2 1.5 3.2 0.7 0.7 0.9 1.0 2772 2254 1.6 3.3 1.0 2.8 2.0 1.1 3.1 2773 10296 0.9 1.7 2.9 5.0 2.1 1.0 1.3 2774 20044 1.0 0.8 2.0 1.0 1.0 1.0 1.0 2775 28806 2.8 1.1 2.1 1.0 0.9 1.2 0.8 2776 17566 7.5 4.2 0.7 0.5 2.5 1.0 2.5 2777 19005 1.0 0.8 1.0 2.1 1.0 1.0 1.0 2778 3567 1.0 1.0 1.0 1.0 1.0 1.0 1.0 2779 21983 0.1 1.0 3.1 25.6 3.4 1.0 4.7 2780 458 1.0 2.1 0.6 1.0 1.6 2.1 2.3 2781 22331 0.6 2.1 0.4 1.0 2.2 1.0 2.8 2782 21411 0.7 1.5 1.0 2.5 1.0 1.0 1.0 2783 22972 1.0 2.2 0.5 1.0 2.2 1.4 2.4 2784 24533 1.0 2.5 1.0 2.0 2.0 2.7 3.2 2785 24853 1.0 2.6 2.1 2.1 2.4 1.3 2.1 2786 23753 0.7 1.5 1.3 2.1 2.0 1.7 2.3 2787 21502 0.3 4.8 1.0 10.8 2.6 1.0 2.9 2788 18180 0.3 0.8 0.8 2.4 0.9 1.4 0.7 2789 23918 0.7 2.3 0.4 1.0 2.4 1.2 3.5 2790 24144 1.0 1.0 1.0 1.0 1.0 1.6 1.0 2791 19996 1.5 2.5 0.7 1.2 2.1 0.9 2.5 2792 11528 1.0 1.0 1.0 2.1 1.0 1.0 1.0 2793 20506 2.2 0.9 3.2 0.8 1.3 1.6 1.0 2794 23833 1.0 0.5 2.1 1.0 1.0 1.0 0.7 2795 20042 3.8 1.6 2.3 0.8 1.0 1.0 1.0 2796 24977 1.0 1.0 2.1 1.0 2.3 1.4 1.4 2797 11646 1.0 1.0 0.8 1000.0 1.0 1.0 1.7 2798 24872 1.0 1.4 0.8 2.5 1.4 1.2 1.3 2799 10577 1.0 1.0 1.0 1.0 1.0 1.0 1.0 2800 21710 1.0 0.2 2.2 0.7 1.6 1.0 1.2 2801 18556 0.0 1.0 1.0 1.0 1.0 1.0 1.0 2802 29433 1.0 0.5 1.0 2.1 1.0 1.0 1.0 2803 29273 1.0 2.2 1.0 2.2 1.0 1.3 1.0 2804 28763 1.6 2.7 1.0 2.2 1.8 1.3 2.5 2805 27887 0.1 0.2 1.1 2.7 0.8 1.0 0.6 2806 27450 2.6 11.3 0.2 1.0 4.4 3.3 7.3 2807 27255 0.6 1.6 0.8 2.3 1.7 1.4 1.5 2808 27226 1.0 1.3 1.0 2.6 1.8 1.0 1.0 2809 26550 4.2 17.9 0.2 1.0 6.9 2.9 9.2 2810 26508 1.0 1.4 1.0 1.0 1.0 1.0 1.0 2811 26483 1.2 2.2 0.6 1.0 2.1 1.4 2.7 2812 26334 1.0 0.5 3.0 1.0 0.6 0.8 0.5 2813 26027 1.0 1.0 1.0 1.5 1.0 1.0 1.0 2814 25977 1.0 1.0 1.0 1.0 1.0 1.0 1.0 2815 25965 1.0 1.0 1.0 1.0 1.0 1.0 1.0 2816 25844 1.0 1.0 1.0 1.0 1.0 1.0 1.0 2817 25834 1000.0 1.0 1.0 1.0. 0.4 1.0 1.0 2818 25816 1.0 1.0 1.0 1.0 1.0 1.0 1.0 2819 25746 1.0 1.0 1.0 1.0 1.0 1.0 1.0 2820 25742 1.0 1.0 1.0 1.0 0.5 1.0 1.0 2821 25741 1.0 1.0 1.0 1.0 1.0 1.0 1.0 2822 25712 1.0 1.0 1.0 1.0 1.0 1.0 1.0 2823 25642 1.0 1.0 1.0 1.0 1.0 1.0 1.0 2824 25621 0.6 0.8 2.1 2.0 1.3 1.2 1.0 2825 25614 1.0 1.0 1.0 1.0 1.0 1.0 1.0 2826 25603 1.0 1.0 1.0 1.0 1.0 1.0 1.0 2827 25556 1.8 0.7 1.0 0.8 1.0 1.0 1.0 2828 25555 1.0 2.9 1.0 1.0 1.5 1.3 1.0 2829 25540 1.0 1.0 1.0 1.2 1.0 1.0 1.0 2830 23576 0.0 1.0 1.0 1.0 1.0 1.5 1.4 2831 22566 1.0 1.0 1.0 1.0 1.0 1.3 1.0 2832 9036 1.9 3.8 0.6 1.8 2.6 1.3 3.1 2833 4164 1.0 1.0 2.2 1.0 1.5 1.0 0.9 2834 4146 0.8 3.7 0.9 4.4 3.3 1.0 4.3 2835 4091 1.0 1.0 1.0 2.5 1.7 1.0 0.9 2836 4072 1.0 1.0 2.1 1.0 5.9 2.0 5.1 2837 4022 3.5 4.5 0.8 1.0 3.0 1.0 3.2 2838 3965 1.9 5.6 0.4 1.0 5.5 2.3 4.1 2839 3954 1.0 2.7 1.3 3.6 2.8 1.9 2.6 2840 3872 1.0 3.2 1.3 2.8 4.0 1.8 3.9 2841 3869 1.0 1.0 5.8 3.8 1.0 0.7 0.6 2842 3838 1.0 1.6 1.2 2.0 2.6 1.7 1.9 2843 3806 0.6 2.6 0.9 3.7 3.0 1.0 3.4 2844 3798 10.2 0.9 2.9 0.3 0.7 1.0 0.4 2845 3792 1.0 1.0 1.0 2.7 2.9 1.0 2.5 2846 3788 1.7 5.4 1.2 3.4 2.5 1.3 2.7 2847 3767 1.1 2.2 0.7 1.7 2.5 1.0 2.5 2848 3458 1.2 3.3 0.7 2.0 2.6 1.0 2.2 2849 3251 0.4 0.5 1.4 2.7 1.4 1.0 1.0 2850 3194 1.0 2.3 1.3 3.1 2.2 1.3 3.2 2851 3102 0.5 3.2 1.0 4.8 2.9 1.0 2.3 2852 3094 11.5 0.8 2.7 0.3 0.6 1.0 0.4 2853 2671 0.8 1.6 1.0 2.2 2.8 1.9 1.0 2854 2634 0.9 2.8 0.4 1.0 3.8 1.7 4.0 2855 2567 4.6 3.3 0.8 0.6 2.6 1.0 3.3 2856 2317 1.0 1.0 2.4 1.0 1.0 1.0 1.1 2857 1958 0.3 0.6 1.0 2.6 0.9 0.8 0.9 2858 1680 0.3 4.7 1.0 17.7 2.7 1.0 4.5 2859 1625 2.2 7.8 0.5 1.8 3.1 1.7 3.4 2860 1445 0.2 0.6 1.0 2.7 0.8 0.9 0.9 2861 1320 4.9 1.0 2.4 0.4 0.6 1.2 0.5 2862 974 0.6 3.1 1.1 3.2 2.4 1.4 3.7 2863 726 1.0 1.0 1.0 1.0 1.0 1.0 1.0 2864 718 0.4 2.6 0.5 2.7 1.6 1.0 1.0 2865 703 1.0 4.1 1.0 2.4 1.6 1.0 1.7 2866 652 2.8 4.4 1.6 2.3 1.0 1.6 1.0 2867 630 6.9 1.0 2.2 0.3 0.6 1.0 0.5 2868 593 1.0 4.3 1.0 2.3 1.0 1.0 1.0 2869 532 1.3 4.7 1.0 2.4 2.6 2.2 4.0 2870 272 0.7 2.7 0.9 3.1 2.4 1.3 4.3 2871 256 0.6 3.2 0.5 1.9 2.8 1.0 3.4 2872 57 0.5 1.4 1.0 2.3 0.9 1.0 0.7

TABLE 27 SEQ ID NO SPOT ID 2506 10594 2507 21851 2508 20990 2509 18641 2510 19037 2511 398 2512 18773 2513 3583 2514 3418 2515 145306 2516 3418 2517 3418 2518 18985 2519 17229 2520 25930 2521 25930 2522 20701 2523 20346 2524 20346 2525 21247 2526 21247 2527 23062 2528 25666 2529 25666 2530 19001 2531 10897 2532 10897 2533 10897 2534 1960 2535 146262 2536 26381 2537 26381 2538 26719 2539 26719 2540 27152 2541 10926 2542 28980 2543 1236 2544 29350 2545 29350 2546 26242 2547 4098 2548 145253 2549 4098 2550 17432 2551 17432 2552 1785 2553 1785 2554 1785 2555 28856 2556 28856 2557 18791 2558 18791 2559 22950 2560 22950 2561 1882 2562 23886 2563 24995 2564 24995 2565 24477 2566 21681 2567 21681 2568 9557 2569 9557 2570 22033 2571 873 2572 17144 2573 26970 2574 26970 2575 21402 2576 27074 2577 27074 2578 10963 2579 10963 2580 29525 2581 29525 2582 25514 2583 25514 2584 26612 2585 26612 2586 24600 2587 9741 2588 9741 2589 9741 2590 23689 2591 23689 2592 22352 2593 23806 2594 12285 2595 27638 2596 27638 2597 9663 2598 9663 2599 26850 2600 10204 2601 10204 2602 10204 2603 25922 2604 25922 2605 26347 2606 26347 2607 20361 2608 20361 2609 28672 2610 28672 2611 25520 2612 25520 2613 1723 2614 1723 2615 28863 2616 25526 2617 25526 2618 27936 2619 27936 2620 26851 2621 25107 2622 25107 2623 25107 2624 24912 2625 24912 2626 25169 2627 25600 2628 25600 2629 28706 2630 28706 2631 26377 2632 26377 2633 19460 2634 25243 2635 20018 2636 20018 2637 918 2638 25027 2639 29089 2640 29089 2641 9141 2642 9141 2643 9141 2644 12005 2645 12148 2646 12148 2647 17394 2648 27017 2649 27017 2650 25809 2651 8719 2652 8719 2653 21030 2654 21030 2655 11436 2656 11436 2657 10374 2658 10374 2659 25861 2660 25861 2661 3317 2662 3317 2663 8743 2664 26240 2665 26240 2666 28562 2667 16877 2668 25955 2669 26308 2670 26308 2671 4140 2672 3436 2673 25612 2674 25612 2675 12257 2676 12257 2677 9111 2678 9111 2679 17620 2680 26025 2681 26025 2682 19271 2683 4151 2684 4151 2685 26569 2686 26569 2687 10344 2688 10344 2689 10344 2690 832 2691 832 2692 12071 2693 12071 2694 12271 2695 11433 2696 20917 2697 25810 2698 12039 2699 12039 2700 25499 2701 25499 2702 25557 2703 25557 2704 9917 2705 19505 2706 17491 2707 10683 2708 10683 2709 1936 2710 828 2711 9558 2712 9558 2713 20164 2714 969 2715 969 2716 9910 2717 2427 2718 19990 2719 20605 2720 20605 2721 10650 2722 10650 2723 25963 2724 25963 2725 25562 2726 25562 2727 3429 2728 2725 2729 19923 2730 20457 2731 20457 2732 24773 2733 24119 2734 3908 2735 3908 2736 8560 2737 8560 2738 9377 2739 9377 2740 17618 2741 12136 2742 17373 2743 18577 2744 18577 2745 3143 2746 17737 2747 17737 2748 20029 2749 20029 2750 18537 2751 18537 2752 12102 2753 12102 2754 8487 2755 9252 2756 9252 2757 25605 2758 25605 2759 29652 2760 10858 2761 1261 2762 4156 2763 4156 2764 3452 2765 3452 2766 2748 2767 2046 2768 2046 2769 2044 2770 2044 2771 1342 2772 1342 2773 1326 2774 1326 2775 9981 2776 9981 2777 27917 2778 8488 2779 22793 2780 22793 2781 26883 2782 26883 2783 11540 2784 17707 2785 20649 2786 20649 2787 24004 2788 24004 2789 11836 2790 11836 2791 11836 2792 24932 2793 19143 2794 19143 2795 26257 2796 26257 2797 21239 2798 21239 2799 16959 2800 2568 2801 25936 2802 25936 2803 23041 2804 9206 2805 25105 2806 25105 2807 24779 2808 22451 2809 22451 2810 22291 2811 22291 2812 21143 2813 24751 2814 24751 2815 24294 2816 24294 2817 24006 2818 24006 2819 25678 2820 25678 2821 22027 2822 29495 2823 29495 2824 24577 2825 24577 2826 24577 2827 23527 2828 17090 2829 25137 2830 23772 2831 1659 2832 8497 2833 25272 2834 21216 2835 21216 2836 21216 2837 11939 2838 11939 2839 11939 2840 9191 2841 3429 2842 24588 2843 4047 2844 28344 2845 28344 2846 27561 2847 3272 2848 26735 2849 26735 2850 24900 2851 24900 2852 9472 2853 9472 2854 9979 2855 21996 2856 22312 2857 11327 2858 18240 2859 18240 2860 21922 2861 21922 2862 22290 2863 10390 2864 10390 2865 2212 2866 20213 2867 20213 2868 24955 2869 19574 2870 19969 2871 8570 2872 18519 2506 9616 2507 9616 2508 17459 2509 17459 2510 25193 2511 25193 2512 25193 2513 25191 2514 22566 2515 4164 2516 4146 2517 4072 2518 4022 2519 3954 2520 3838 2521 3806 2522 3798 2523 3792 2524 3788 2525 3458 2526 3194 2527 3102 2528 25191 2529 25191 2530 9448 2531 9448 2532 25224 2533 20218 2534 3089 2535 3089 2536 19953 2537 19953 2538 22362 2539 25516 2540 25516 2541 25757 2542 24814 2543 21994 2544 27117 2545 22745 2546 24233 2547 2001 2548 2001 2549 2001 2550 17147 2551 21214 2552 21214 2553 21214 2554 26422 2555 21965 2556 25541 2557 25541 2558 18302 2559 18302 2560 24049 2561 24049 2562 26326 2563 26326 2564 2254 2565 162502 2566 10296 2567 20044 2568 28806 2569 17566 2570 17566 2571 19005 2572 3567 2573 159223 2574 3567 2575 3567 2576 458 2577 21411 2578 22972 2579 24853 2580 21502 2581 18180 2582 23918 2583 24144 2584 19996 2585 11528 2586 20506 2587 20506 2588 23833 2589 20042 2590 20042 2591 11646 2592 10577 2593 10577 2594 18556 2595 29433 2596 28763 2597 27450 2598 27450 2599 27255 2600 26550 2601 26550 2602 26508 2603 26334 2604 26334 2605 26027 2606 26027 2607 25977 2608 25977 2609 25965 2610 25965 2611 25844 2612 25844 2613 25834 2614 25816 2615 25746 2616 25712 2617 25621 2618 25621 2619 25614 2620 25614 2621 25603 2622 25603 2623 25556 2624 25556 2625 25555 2626 25555 2627 3094 2628 2567 2629 1958 2630 1680 2631 1445 2632 1320 2633 974 2634 652 2635 630 2636 593 2637 256

Example 41 Cyclin G Associated Kinase (GAK)

A gene or product thereof called cyclin G associated kinase, or GAK, was identified as being overexpressed in 3D T4-2 cultures relative to both 3D S1 cultures (ratio: 7.9296) and 2D T4-2 cultures (ratio: 34.6682) (Sample ID RG:1056692:10012:C11, Spot ID 19990). GAK corresponds to Genbank Accession number XM_(—)003450.

Example 42 Antisense Regulation of GAK Expression

Additional functional information on GAK was generated using antisense knockout technology. A number of different oligonucleotides complementary to GAK mRNA were designed (AS) with corresponding controls (RC): GGAATCACCGCTTTGCCATCTTCAA (SEQ ID NO:3005;CHIR159-1AS, gak:P1868AS), AACTTCTACCGTTTCGCCACTAAGG (SEQ ID NO:3006; CHIR159-1RC, gak:P1868RC); GACCGTGTACTGCGTGTCGTGCG (SEQ ID NO:3007; CHIR159-7AS, gak:P0839AS) and GCGTGCTGTGCGTCATGTGCCAG (SEQ ID NO: 3008; CHIR159-7RC, gak:P0839RC), and tested for their ability to suppress expression of GAK in human malignant colorectal carcinoma SW620 cells, human breast cancer MDA231 cells, and human breast cancer T4-2 cells. For each transfection mixture, a carrier molecule, preferably a lipitoid or cholesteroid, was prepared to a working concentration of 0.5 mM in water, sonicated to yield a uniform solution, and filtered through a 0.45 μm PVDF membrane. The antisense or control oligonucleotide was then prepared to a working concentration of 100 μM in sterile Millipore water. The oligonucleotide was further diluted in OptiMEM™ (Gibco/BRL), in a microfuge tube, to 2 μM, or approximately 20 μg oligo/ml of OptiMEM™. In a separate microfuge tube, lipitoid or cholesteroid, typically in the amount of about 1.5-2 nmol lipitoid/μg antisense oligonucleotide, was diluted into the same volume of OptiMEM™ used to dilute the oligonucleotide. The diluted antisense oligonucleotide was immediately added to the diluted lipitoid and mixed by pipetting up and down. Oligonucleotide was added to the cells to a final concentration of 300 nM.

The level of target mRNA (GAK) in the transfected cells was quantitated in the cancer cell lines using the methods using primers CHIR159_(—)2896 (GCCGTCTTCAGGCAACAACTCCCA; SEQ ID NO: 3009; forward) and CHIR159_(—)3089 (TGCTGGACGAGGCTGTCATCTTGC; SEQ ID NO: 3010; reverse). RNA was extracted as above according to manufacturer's directions.

Quantitative PCR (qPCR) was performed by first isolating the RNA from the above mentioned tissue/cells using a Qiagen RNeasy mini prep kit. A total of 0.5 micrograms of RNA was used to generate a first strand cDNA using Stratagene MuLV Reverse Transcriptase, using recommended concentrations of buffer, enzyme, and Rnasin. Concentrations and volumes of dNTP, and oligo dT, or random hexamers were lower than recommended to reduce the level of background primer dimerization in the qPCR.

The cDNA is then used for qPCR to determine the levels of expression of GAK using the GeneAmp 7000 by ABI as recommended by the manufacturer. Primers for actin were also used in order to normalized the values, and eliminate possible variations in cDNA template concentrations, pipetting error, etc.

For each 20 μl reaction, extracted RNA (generally 0.2-1 μg total) was placed into a sterile 0.5 or 1.5 ml microcentrifuge tube, and water was added to a total volume of 12.5 μl. To each tube was added 7.5 μl of a buffer/enzyme mixture, prepared by mixing (in the order listed) 2.5 μl H₂O, 2.0 μl 10× reaction buffer, 10 μl oligo dT (20 pmol), 1.0 μl dNTP mix (10 mM each), 0.5 μl RNAsin® (20 u) (Ambion, Inc., Hialeah, Fla.), and 0.5 μl MMLV reverse transcriptase (50 u) (Ambion, Inc.). The contents were mixed by pipetting up and down, and the reaction mixture was incubated at 42° C. for 1 hour. The contents of each tube were centrifuged prior to amplification.

An amplification mixture was prepared by mixing in the following order: 1× PCR buffer II, 3 mM MgCl₂, 140 μM each dNTP, 0.175 pmol each oligo, 1:50,000 dil of_SYBR® Green, 0.25 mg/ml BSA, 1 unit Taq polymerase, and H₂O to 20 μl. (PCR buffer II is available in 10× concentration from Perkin-Elmer, Norwalk, Conn.). In 1× concentration it contains 10 mM Tris pH 8.3 and 50 mM KCl. SYBR® Green (Molecular Probes, Eugene, Oreg.) is a dye which fluoresces when bound to double stranded DNA. As double stranded PCR product is produced during amplification, the fluorescence from SYBR® Green increases. To each 20 μl aliquot of amplification mixture, 2 μl of template RT was added, and amplification was carried out according to standard protocols.

Table 19 shows that the antisense oligonucleotides described above reduced expression of GAK mRNA as compared to controls in all three cell lines. GAK mRNA reduction ranged from about 50% to about 90%, as compared to cells transfected with reverse (i.e. sense) control oligonucleotides. TABLE 19 antisense regulation of GAK mRNA Gene Actin Oligo Cell Line Message Message Ratio Percent KO CHIR159-1AS SW620 0.0923 0.669 0.138 90.7 CHIR159-1RC SW620 1.01 0.680 1.49 CHIR159-7AS SW620 0.0555 0.678 0.082 85.4 CHIR159-7RC SW620 0.335 0.598 0.560 CHIR159-1AS MDA231 0.358 0.687 0.521 59.3 CHIR159-1RC MDA231 1.00 0.784 1.28 CHIR159-7AS MDA231 0.262 0.674 0.389 69.4 CHIR159-7RC MDA231 0.840 0.659 1.27 CHIR159-1AS T4-2 0.307 0.707 0.434 72.9 CHIR159-1RC T4-2 1.23 0.770 1.60 CHIR159-7AS T4-2 0.214 0.649 0.330 49.8 CHIR159-7RC T4-2 0.506 0.770 0.657

Reduction of GAK protein by antisense polynucleotides in SW620, MDA231 and T4-2 was confirmed using an antibody that specifically recognizes GAK. FIG. 38 shows a western (i.e. protein) blot of protein extracts of the above cell lines decorated with anti-GAK antibodies. GAK protein expression is reduced in cell lines receiving GAK antisense oligonucleotides.

Example 43 Role of GAK in Anchorage Independent Cell Growth

The effect of GAK gene expression upon anchorage-independent cell growth of SW620 and MBA-231 cells was measured by colony formation in soft agar. Soft agar assays were performed by first coating a non-tissue culture treated plate with PolyHEMA to prevent cells from attaching to the plate. Non-transfected cells were harvested using 0.05% trypsin and washing twice in media. The cells are counted using a hemacytometer and resuspended to 10⁴ per ml in media. 50 μl aliquots are placed in poly-HEMA coated 96-well plates and transfected. For each transfection mixture, a carrier molecule, preferably a lipitoid or cholesteroid, was prepared to a working concentration of 0.5 mM in water, sonicated to yield a uniform solution, and filtered through a 0.45 μm PVDF membrane. The antisense or control oligonucleotide was then prepared to a working concentration of 100 μM in sterile Millipore water. The oligonucleotide was further diluted in OptiMEM™ (Gibco/BRL), in a microfuge tube, to 2 μM, or approximately 20 μg oligo/ml of OptiMEM™. In a separate microfuge tube, lipitoid or cholesteroid, typically in the amount of about 1.5-2 nmol lipitoid/μg antisense oligonucleotide, was diluted into the same volume of OptiMEM™ used to dilute the oligonucleotide. The diluted antisense oligonucleotide was immediately added to the diluted lipitoid and mixed by pipetting up and down. Oligonucleotide was added to the cells to a final concentration of 300 nM. Following transfection (˜30 minutes), 3% GTG agarose is added to the cells for a final concentration of 0.35% agarose. After the cell layer agar solidifies, 100 μl of media is dribbled on top of each well. Colonies form in 7 days. For a read-out of growth, 20 μl of Alamar Blue is added to each well and the plate is shaken for 15 minutes. Fluorecence readings (530nm excitation 590 nm emission) are taken after incubation for 6-24 hours.

The data presented in Table 20 shows that the application of GAK antisense oligonucleotides to SW620 and MDA 231 cells results in inhibition of colony formation and shows that GAK plays a role in production anchorage-independent cell growth. Table 4 shows the average fluorescence reading for several experiments. The standard deviation (St. Dev) of the fluorescence reading and coefficient of variation (% CV) is also shown. TABLE 20 GAK and anchorage-independent cell growth. % Oligo Cell Line Average St. Dev CV Blank SW620 12868.17 208.78 1.78 Untreated SW620 31075.17 1944.36 7.66 Pos Control SW620 5717.17 1108.71 23.75 Neg Control SW620 7576.17 465.95 7.63 Chir159-1AS SW620 9701.5 2281.36 28.8 Chir159-1RC SW620 17765.5 1958.45 13.5 Blank MDA231 12726.83 232.45 2 Untreated MDA231 87272.17 0 0 Pos Control MDA231 10645.17 1591.08 18.31 Neg Control MDA231 24159.5 2850.58 14.45 Chir159-1AS MDA231 8613.5 4852.76 69 Chir159-1RC MDA231 17859.17 1535.55 10.53

Example 44 DKFZp566I133 (DKFZ)

Several previously uncharacterized genes were identified as being induced in these experiments. One such gene was represented by two spots, Spot ID Nos 22793 and 26883 (gene assignment DKFZp556I133). This gene was expressed at a ratio of about 2.2 in two 2-dimensional (2D) T4-2 vs. 2D S1 experiments, and also at a ratio of about 2 when 3-dimensional (3D) T4-2 cells were compared to the various tumor reversion cultures. However, the ratio of expression increased to an average of 3.2 when 3-dimensional (3D) T4-2 cultures were compared to 2D S1 cultures. In contrast, there was essentially no difference in expression levels when 3D S1 cultures were compared to 2D S1 cultures, suggesting that expression of this gene is specifically elevated in the tumorigenic cell line T4-2, and even further elevated when the tumorigenic cell line is grown in three dimensional cultures (see Table 21). TABLE 21 Spot 2D T4-2/ 3D T42/ 3D S1/ 3D T4-2/ 3D T4-2/ 3D T4-2/B1 3D T4-2/ ID 2D S1 3D S1 2D S1 2D T4-2 EGFRAb integrin Ab Tyr 22893 1.90387 2.64711 0.522161 1 2.17956 1.75287 2.055538 26883 2.43428 3.74613 0.524466 1 2.467573 2.029468 2.002817

These array data were confirmed by qPCR using the methods described above and the gene specific PCR primers CHIR180_(—)1207 ACAGGGAGAAAACTGGTTGTCCTGG (SEQ ID NO:3011; Forward) and CHIR180_(—)1403 AAGGCAGAACCCATCCACTCCAA (SEQ ID NO:3012; Reverse). Independent cultures were used for these experiments, and data was normalized to B-catenin. These data are shown in Table 22. TABLE 22 3D B1 Integrin 3D 2D S1 2D T4-2 3D S1 3D T4-2 3D EGFRAb Ab Tyr 0.165 0.421 0.14 0.475 0.231 0.175 0.174

DKFZ corresponds to Genbank Accession numbers NP_(—)112200, AAH09758, and NM_(—)030938. Orthologs of DKFZ are identified in species other than Homo sapiens include NM_(—)138839 from Rattus norvegicus.

Analysis of the sequence of DKFZ using a transmembrane helix prediction algorithm (Sonhammer, et al, A hidden Markov model for predicting transmembrane helices in protein sequences, In Proc. of Sixth Int. Conf. on Intelligent Systems for Molecular Biology, p. 175-82, Ed. J. Glasgow, T. Littlejohn, F. Major, R. Lathrop, D. Sankoff, and C. Sensen, Menlo Park, CA: AAAI Press, 1998) indicates that the DKFZ protein has six transmembrane regions (FIG. 18), and, as such, is likely to be a transmembrane protein.

Example 45 Antisense Regulation of DKFZ Expression

Additional functional information on DKFZ was generated using antisense knockout technology. A number of different oligonucleotides complementary to DKFZ mRNA were designed (AS) with corresponding controls (RC): GCTGCTGGATTCGTTTGGCATAACT (SEQ ID NO: 3013; CHIR180-7AS, DKFZp566I1:P1301AS), TCAATACGGTTTGCTTAGGTCGTCG (SEQ ID NO: 3014; CHIR180-7RC, DKFZp566I1:P1301RC), TCTCCTCTGAGTTCAACCGCTGCT (SEQ ID NO: 3015; CHIR180-8AS, DKFZp566I1:P1320AS) and TCGTCGCCAACTTGAGTCTCCTCT (SEQ ID NO: 3016; CHIR180-8RC, DKFZp566I1:P1320AS), and tested for their ability to suppress expression of DKFZ in human malignant colorectal carcinoma SW620 cells, human breast cancer MDA231 cells, and human breast cancer T4-2 cells, as described above.

Table 23 shows that the antisense (AS) oligonucleotides described above reduced expression of DKFZ mRNA as compared to controls in all three cell lines. DKFZ mRNA reduction ranged from about 95% to about 99%, as compared to cells transfected with reverse (i.e. sense) control (RC) oligonucleotides. TABLE 23 antisense regulation of DKFZ mRNA Gene Actin Percent Oligo Cell Line Message Message Ratio KO CHIR180-7AS SW620 0.0157 0.772 0.020 99.3 CHIR180-7RC SW620 1.99 0.736 2.70 CHIR180-8AS SW620 0.0387 0.681 0.057 97.9 CHIR180-8RC SW620 1.89 0.703 2.69 CHIR180-7AS MDA231 0.0471 3.58 0.013 98.5 CHIR180-7RC MDA231 1.99 2.33 0.854 CHIR180-8AS MDA231 0.00935 1.74 0.00537 99.5 CHIR180-8RC MDA231 1.14 1.01 1.13 CHIR180-7AS T4-2 0.119 0.667 0.178 95.4 CHIR180-7RC T4-2 2.8 0.728 3.85 CHIR180-8AS T4-2 0.0852 0.751 0.113 95.6 CHIR180-8RC T4-2 1.6 0.620 2.58

Example 46 Effect of DKFZ Expression on Cell Proliferation

The effect of gene expression on the inhibition of cell proliferation was assessed in metastatic breast cancer cell line MDA-231 and breast cancer cell line T4-2.

Cells were plated to approximately 60-80% confluency in 96-well dishes. Antisense or reverse control oligonucleotide was diluted to 2 μM in OptiMEM™ and added to OptiMEM™ into which a delivery vehicle, preferably a lipitoid or cholesteroid, had been diluted. The oligo/delivery vehicle mixture was then further diluted into medium with serum on the cells. The final concentration of oligonucleotide for all experiments was 300 nM, and the final ratio of oligo to delivery vehicle for all experiments was 1.5 nmol lipitoid/μg oligonucleotide.

Antisense oligonucleotides were prepared. Cells were transfected for 4 hours or overnight at 37° C. and the transfection mixture was replaced with fresh medium. Plates are incubated for 4 days, with a plate harvested for each day0-day4. To determine differences in cell number, a CyQuant Cell Proliferation Assay kit (Molecular Probes) was used per manufacturer's instructions. Fluorecence readings (480 nm excitation 520 nm emission) are taken after incubation for 5 minutes.

The results of these assays are shown in Tables 23A and 24. The data show that DKFZ antisense polynucleotides significantly reduce cell proliferation as compared to controls, and, as such, DKFZ plays a role in production or maintenance of the cancerous phenotype in cancerous breast cells. TABLE 23A Cell proliferation Ave Day Ave Ave Av3 Ave Oligo Cell Line 0 Day 1 Day 2 Day 3 Day 4 Untreated MDA231 4233 4858 9544 10981 16776 Untreated MDA231 3849 4036 8686 9855 14865 Pos Control MDA231 3630 2236 3564 4536 7477 Neg Control MDA231 4913 5127 8331 8887 13620 CHIR180-7AS MDA231 3848 3476 6942 8715 11925 CHIR180-7RC MDA231 4895 4700 8484 10318 14226 Untreated T4-2 4062 3389 5438 10579 15617 Untreated T4-2 4209 3802 6346 11802 16275 Pos Control T4-2 3985 2712 4081 6404 9685 Neg Control T4-2 4051 3901 4356 9425 12964 CHIR180-7AS T4-2 3792 3201 3849 7376 10911 CHIR180-7RC T4-2 3967 3840 4321 8382 12293

TABLE 24 Standard Deviations P-Value of T-Test Oligo Day 0 Day 1 Day 2 Day 3 Day 4 Day 0 Day 1 Day 2 Day 3 Day 4 Untreated 337 269 299 697 1333 0.1306 0.1063 0.1804 0.0926 0.1225 Untreated 99 631 867 547 1047 0.1306 0.1063 0.1804 0.0926 0.1225 Pos 94 118 89 441 974 0.0000 0.0001 0.0003 0.0001 0.0010 Control Neg 2 252 697 195 780 0.0000 0.0001 0.0003 0.0001 0.0010 Control CHIR180-7AS 292 16 435 398 418 0.0072 0.0276 0.0059 0.0140 0.0028 CHIR180-7RC 208 6 244 533 440 0.0072 0.0276 0.0059 0.0140 0.0028 Untreated 64 283 789 1593 1226 0.2550 0.0921 0.1257 0.2794 0.4352 Untreated 22 158 205 577 478 0.2550 0.0921 0.1257 0.2794 0.4352 Pos 122 213 6 475 957 0.4320 0.0065 0.2624 0.0051 0.0293 Control Neg 47 335 464 809 1417 0.4320 0.0065 0.2624 0.0051 0.0293 Control CHIR180-7AS 170 679 263 127 1330 0.2638 0.0976 0.3516 0.0040 0.0039 CHIR180-7RC 22 453 646 579 884 0.2638 0.0976 0.3516 0.0040 0.0039

Example 47 Role of DKFZ in Anchorage Independent Cell Growth

The effect of DKFZ gene expression upon anchorage-independent cell growth of MDA435 and MCF7 human breast cancer cells was measured by colony formation in soft agar. Soft agar assays were conducted by the method described for GAK, above.

The data presented in Table 25 shows that the application of DKFZ antisense oligonucleotides to MDA435 and MCF7 cells results in inhibition of colony formation and shows that DKFZ plays a role in anchorage-independent cell growth of cancer cells. Table 25 shows the average fluorescence reading for several experiments. The standard deviation (St. Dev) of the fluorescence reading and coefficient of variation (% CV) and probability (P-value) is also shown. TABLE 25 Oligo Cell Line Average St. Dev % CV P-Value Untreated MDA435 31190 5838 19 0.1342 Untreated MDA435 38623 3620 9 0.1342 Pos Control MDA435 4776 818 17 0.0156 Neg Control MDA435 16315 481 3 0.0156 Chir180-7AS MDA435 21161 3439 16 0.0274 Chir180-7RC MDA435 28868 1902 7 0.0274 Untreated MCF7 18954 1478 8 0.1476 Untreated MCF7 14383 4163 29 0.1476 Pos Control MCF7 1036 194 19 0.0036 Neg Control MCF7 9478 2382 25 0.0036 Chir180-7AS MCF7 4752 2002 42 0.0139 Chir180-7RC MCF7 9570 18 0 0.0139

The effect of DKFZ gene expression upon invasiveness of MDA231 human breast cancer cells was measured by a matrigel assay. A 3-dimensional reconstituted basement membrane culture of cells was generated as described previously (Peterson et al., (1992) Proc. Natl. Acad. Sci. USA 89:9064-9068) using a commercially prepared reconstituted basement membrane (Matrigel; Collaborative Research, Waltham, Mass.) and examined using methods well known in the art.

Table 26 (quantitated using Alamar Blue similar to the soft agar assay) and FIG. 40 provides exemplary results of the Matrigel invasion/motility assay to test the invasiveness of MDA231 cells with reduced expression of DKFZ. In general, these data show that a reduction in the expression of DKFZ significantly decreases the invasiveness of MDA231 cells. TABLE 26 Oligo Cell Line Average St. Dev % CV P-Value Untreated MDA231 28316 13663 48 0.9080 Untreated MDA231 26840 15669 58 0.9080 Pos Control MDA231 2756 487 18 0.0002 Neg Control MDA231 14301 1386 10 0.0002 Chir180-7AS MDA231 10508 1963 19 0.0287 Chir180-7RC MDA231 14310 153 1 0.0287

Example 48 Expression of DKFZ in Cancer Tissues

The following peptides were used for polyclonal antibody production: peptide 809: gvhqqyvqriek (SEQ ID NO:2885), corresponding to amino acids 97-108 of the DKFZ protein and peptide 810: sgaepddeeyqef (SEQ ID NO: 2886), corresponding to amino acids 215-227 of the DKFZ protein.

Antibodies specific for DKFZ are used in FACS and immunolocalization analysis to show that DKFZ is associated with membrane, and up-regulated in cancer tissues of biopsies from cancer patients.

Further, antibodies specific for DKFZ are used to modulate DKFZ activity in cancerous breast, and is further used, alone or conjugated to a toxic moiety, as a treatment for breast cancer.

Example 49 Source of Biological Materials

The biological materials used in the experiments that led to the present invention are described below.

Source of Patient Tissue Samples

Normal and cancerous tissues were collected from patients using laser capture microdissection (LCM) techniques, which techniques are well known in the art (see, e.g., Ohyama et al. (2000) Biotechniques 29:530-6; Curran et al. (2000) Mol. Pathol. 53:64-8; Suarez-Quian et al. (1999) Biotechniques 26:328-35; Simone et al. (1998) Trends Genet 14:272-6; Conia et al. (1997) J. Clin. Lab. Anal. 11:28-38; Emmert-Buck et al. (1996) Science 274:998-1001). Table 28 provides information about each patient from which colon tissue samples were isolated, including: the Patient ID (“PT ID”) and Path ReportID (“Path ID”), which are numbers assigned to the patient and the pathology reports for identification purposes; the group (“Grp”) to which the patients have been assigned; the anatomical location of the tumor (“Anatom Loc”); the primary tumor size (“Size”); the primary tumor grade (“Grade”); the identification of the histopathological grade (“Histo Grade”); a description of local sites to which the tumor had invaded (“Local Invasion”); the presence of lymph node metastases (“Lymph Met”); the incidence of lymph node metastases (provided as a number of lymph nodes positive for metastasis over the number of lymph nodes examined) (“Lymph Met Incid”); the regional lymphnode grade (“Reg Lymph Grade”); the identification or detection of metastases to sites distant to the tumor and their location (“Dist Met & Loc”); the grade of distant metastasis (“Dist Met Grade”); and general comments about the patient or the tumor (“Comments”). Histopathology of all primary tumors indicated the tumor was adenocarcinoma except for Patient ID Nos. 130 (for which no information was provided), 392 (in which greater than 50% of the cells were mucinous carcinoma), and 784 (adenosquamous carcinoma). Extranodal extensions were described in three patients, Patient ID Nos. 784, 789, and 791. Lymphovascular invasion was described in Patient ID Nos. 128, 228, 278, 517, 534, 784, 786, 789, 791, 890, and 892. Crohn's-like infiltrates were described in seven patients, Patient ID Nos. 52, 264, 268, 392, 393, 784, and 791.

Table 28: TABLE 28 Lymph Reg Dist Dist Path Anatom Histo Lymph Met Lymph Met Met Pt ID ID Grp Loc Size Grade Grade Local Invasion Met Incid Grade & Loc Grade Comment 10 16 III Cecum 8.5 T3 G2 through Pos 1/17 N1 Neg M0 Moderately muscularis propria differentiated approaching pericolic fat, but not at serosal surface 15 21 III Ascending 4.0 T3 G2 Extending into Pos 3/8  N1 Neg MX invasive colon subserosal adipose adeno- tissue carcinoma, moderately differentiated; focal perineural invasion is seen 52 71 II Cecum 9.0 T3 G3 Invasion through Neg 0/12 N0 Neg M0 Hyperplastic muscularis polyp in propria, subserosal appendix. involvement; ileocec. valve involvement 121 140 II Sigmoid 6 T4 G2 Invasion of Neg 0/34 N0 Neg M0 Perineural muscularis propria invasion; donut into serosa, anastomosis involving Neg. One submucosa of tubulovillous urinary bladder and one tubular adenoma with no high grade dysplasia. 125 144 II Cecum 6 T3 G2 Invasion through Neg 0/19 N0 Neg M0 patient history the muscularis of metastatic propria into melanoma suserosal adipose tissue. Ileocecal junction. 128 147 III Transverse 5.0 T3 G2 Invasion of Pos 1/5  N1 Neg M0 colon muscularis propria into percolonic fat 130 149 Splenic 5.5 T3 through wall and Pos 10/24  N2 Neg M1 flexure into surrounding adipose tissue 133 152 II Rectum 5.0 T3 G2 Invasion through Neg 0/9  N0 Neg M0 Small separate muscularis propria tubular into non- adenoma (0.4 cm) peritonealized pericolic tissue; gross configuration is annular. 141 160 IV Cecum 5.5 T3 G2 Invasion of Pos 7/21 N2 Pos - M1 Perineural muscularis propria Liver invasion into pericolonic identified adipose tissue, but adjacent to not through serosa. metastatic Arising from adenocarcinoma. tubular adenoma. 156 175 III Hepatic 3.8 T3 G2 Invasion through Pos 2/13 N1 Neg M0 Separate flexure mucsularis propria tubolovillous into and tubular subserosa/pericolic adenomas adipose, no serosal involvement. Gross configuration annular. 228 247 III Rectum 5.8 T3 G2 to Invasion through Pos 1/8  N1 Neg MX Hyperplastic G3 muscularis propria polyps to involve subserosal, perirectoal adipose, and serosa 264 283 II Ascending 5.5 T3 G2 Invasion through Neg 0/10 N0 Neg M0 Tubulovillous colon muscularis propria adenoma with into subserosal high grade adipose tissue. dysplasia 266 285 III Transverse 9 T3 G2 Invades through Neg 0/15 N1 Pos - MX colon muscularis propria Mesen- to involve teric pericolonic deposit adipose, extends to serosa. 267 286 III Ileocecal 4.5 T2 G2 Confined to Pos 2/12 N1 Neg M0 muscularis propria 268 287 I Cecum 6.5 T2 G2 Invades full Neg 0/12 N0 Neg M0 thickness of muscularis propria, but mesenteric adipose free of malignancy 278 297 III Rectum 4 T3 G2 Invasion into Pos 7/10 N2 Neg M0 Descending perirectal adipose colon polyps, tissue. no HGD or carcinoma identified.. 295 314 II Ascending 5.0 T3 G2 Invasion through Neg 0/12 N0 Neg M0 Melanosis coli colon muscularis propria and diverticular into percolic disease. adipose tissue. 296 315 III Cecum 5.5 T3 G2 Invasion through Pos 2/12 N1 Neg M0 Tubulovillous muscularis propria adenoma (2.0 cm) and invades with no pericolic adipose high grade tissue. Ileocecal dysplasia. Neg. junction. liver biopsy. 300 319 III Descend- 5.2 T2 G2 through the Pos 2/2  N1 Neg M0 ing muscularis propria colon into pericolic fat 322 341 II Sigmoid 7 T3 G2 through the Neg 0/5  N0 Neg M0 vascular muscularis propria invasion is into pericolic fat identified 339 358 II Recto- 6 T3 G2 Extends into Neg 0/6  N0 Neg M0 1 hyperplastic sigmoid perirectal fat but polyp identified does not reach serosa 341 360 II Ascending 2 cm T3 G2 Invasion through Neg 0/4  N0 Neg MX colon invasive muscularis propria to involve pericolonic fat. Arising from villous adenoma. 356 375 II Sigmoid 6.5 T3 G2 Through colon Neg 0/4  N0 Neg M0 wall into subserosal adipose tissue. No serosal spread seen. 360 412 III Ascending 4.3 T3 G2 Invasion thru Pos 1/5  N1 Neg M0 Two mucosal colon muscularis propria polyps to pericolonic fat 392 444 IV Ascending 2 T3 G2 Invasion through Pos 1/6  N1 Pos - M1 Tumor arising colon muscularis propria Liver at prior into subserosal ileocolic adipose tissue, not surgical serosa. anastomosis. 393 445 II Cecum 6.0 T3 G2 Cecum, invades Neg 0/21 N0 Neg M0 through muscularis propria to involve subserosal adipose tissue but not serosa. 413 465 IV Cecum 4.8 T3 G2 Invasive through Neg 0/7  N0 Pos - M1 rediagnosis of muscularis to Liver oophorectomy involve periserosal path to fat; abutting metastatic ileocecal junction. colon cancer. 452 504 II Ascending 4 T3 G2 through Neg 0/39 N0 Neg M0 colon muscularis propria approaching pericolic fat, but not at serosal surface 505 383 IV 7.5 T3 G2 Invasion through Pos 2/17 N1 Pos - M1 Anatomical muscularis propria Liver location of involving pericolic primary not adipose, serosal notated in surface uninvolved report. Evidence of chronic colitis. 517 395 IV Sigmoid 3 T3 G2 penetrates Pos 6/6  N2 Neg M0 No mention of muscularis distant met in propria, involves report pericolonic fat. 534 553 II Ascending 12 T3 G3 Invasion through Neg 0/8  N0 Neg M0 Omentum with colon the muscularis fibrosis and fat propria involving necrosis. Small pericolic fat. bowel with Serosa free of acute and tumor. chronic serositis, focal abscess and adhesions. 546 565 IV Ascending 5.5 T3 G2 Invasion through Pos 6/12 N2 Pos - M1 colon muscularis propria Liver extensively through submucosal and extending to serosa. 577 596 II Cecum 11.5 T3 G2 Invasion through Neg 0/58 N0 Neg M0 Appendix the bowel wall, dilated and into suberosal fibrotic, but not adipose. Serosal involved by surface free of tumor tumor. 695 714 II Cecum 14.0 T3 G2 extending through Neg 0/22 N0 Neg MX moderately bowel wall into differentiated serosal fat adenocarcinoma with mucinous diferentiation (% not stated), tubular adenoma and hyperplstic polyps present, 784 803 IV Ascending 3.5 T3 G3 through Pos 5/17 N2 Pos - M1 invasive poorly colon muscularis propria Liver differentiated into pericolic soft adenosquamous tissues carcinoma 786 805 IV Descend- 9.5 T3 G2 through Neg 0/12 N0 Pos - M1 moderately ing muscularis propria Liver differentiated colon into pericolic fat, invasive but not at serosal adenocarcinoma surface 787 806 II Recto- 2.5 T3 G2-G3 Invasion of Neg N0 Neg MX Peritumoral sigmoid muscularis propria lymphocytic into soft tissue response; 5 LN examined in pericolic fat, no metastatases observed. 789 808 IV Cecum 5.0 T3 G2-G3 Extending through Pos 5/10 N2 Pos - M1 Three fungating muscularis propria Liver lesions into pericolonic fat examined. 790 809 IV Rectum 6.8 T3 G1-G2 Invading through Pos 3/13 N1 Pos - M1 muscularis propria Liver into perirectal fat 791 810 IV Ascending 5.8 T3 G3 Through the Pos 13/25  N2 Pos - M1 poorly colon muscularis propria Liver differentiated into pericolic fat invasive colonic adenocarcinoma 888 908 IV Ascending 2.0 T2 G1 Into muscularis Pos 3/21 N0 Pos - M1 well to colon propria Liver moderately differentiated adenocarcinomas; this patient has tumors of the ascending colon and the sigmoid colon 889 909 IV Cecum 4.8 T3 G2 Through Pos 1/4  N1 Pos - M1 moderately muscularis propria Liver differentiated int subserosal adenocarcinoma tissue 890 910 IV Ascending T3 G2 Through Pos 11/15  N2 Pos - M1 colon muscularis propria Liver into subserosa. 891 911 IV Rectum 5.2 T3 G2 Invasion through Pos 4/15 N2 Pos - M1 Perineural muscularis propria Liver invasion into perirectal soft present. tissue 892 912 IV Sigmoid 5.0 T3 G2 Invasion into Pos 1/28 N1 Pos - M1 Perineural pericolic sort Liver, invasion tissue. Tumor left present, focally invading and extensive. skeletal muscle right Patient with a attached to colon. lobe, history of colon omen- cancer. tum 893 913 IV Transverse 6.0 T3 G2-G3 Through Pos 14/17  N2 Pos - M1 Perineural colon muscularis propria Liver invasion focally into pericolic fat present. Omentum mass, but resection with no tumor identified. 989 1009 IV Sigmoid 6.0 T3 G2 Invasion through Pos 1/7  N1 Pos - M1 Primary colon wall and Liver adenocarcinoma focally involving arising from subserosal tissue. tubulovillous adenoma.

Source of Polynucleotides on Arrays

Polynucleotides for use on the arrays were obtained from both publicly available sources and from cDNA libraries generated from selected cell lines and patient tissues. Table 29 provides information about the polynucleotides on the arrays including: (1) the “SEQ ID NO” assigned to each sequence for use in the present specification; (2) the spot identification number (“Spot ID”), an internal reference that serves as a unique identifier for the spot on the array; (3) the “Clone ID” assigned to the clone from which the sequence was isolated; and (4) the “MAClone ID” assigned to the clone from which the sequence was isolated. The sequences corresponding to the SEQ ID NOS are provided in the Sequence Listing. TABLE 29 SEQ ID NO Spot ID Clone ID MAClone ID 3022 18 M00026919B:A10 MA40:F01 3023 20 M00026919B:E07 MA40:G01 3024 22 M00026919D:F04 MA40:H01 3025 54 M00026914D:G06 MA40:A01 3026 56 M00026950A:A09 MA40:D07 3027 67 M00003820C:A09 MA244:B01 3028 73 M00001673A:G03 MA244:E01 3029 115 M00007939A:A12 MA27:B07 3030 119 M00007939A:B11 MA27:D07 3031 127 M00007939B:G03 MA27:H07 3032 166 M00007997D:G08 MA29:C01 3033 220 M00026894C:E11 MA39:F07 3034 238 M00001391A:C05 MA15:G01 3035 294 M00006818A:A06 MA240:C01 3036 393 M00023278A:F09 MA36:E01 3037 405 M00023299A:G01 MA36:C07 3038 411 M00023301A:A11 MA36:F07 3039 453 M00008050A:D12 MA30:C01 3040 460 M00022135A:C04 MA35:F01 3041 462 M00022137A:A05 MA35:G01 3042 466 M00022176C:A07 MA35:A07 3043 471 M00008077B:A08 MA30:D07 3044 477 M00008077C:D09 MA30:G07 3045 492 M00022081C:E09 MA34:F01 3046 495 M00001662A:G06 MA24:H01 3047 504 M00022102B:B11 MA34:D07 3048 506 M00022102B:E08 MA34:E07 3049 556 M00022569D:G06 MA22:F01 3050 577 M00001358B:B11 MA14:A01 3051 578 M00001429A:G04 MA16:A01 3052 579 M00001358B:F05 MA14:B01 3053 582 M00001429C:C03 MA16:C01 3054 585 M00001359D:B04 MA14:E01 3055 587 M00001360A:E10 MA14:F01 3056 589 M00001360C:B05 MA14:G01 3057 590 M00001430B:F01 MA16:G01 3058 592 M00001430C:A02 MA16:H01 3059 594 M00001445C:H05 MA16:A07 3060 596 M00001445D:D07 MA16:B07 3061 605 M00001374D:D10 MA14:G07 3062 607 M00001375A:A08 MA14:H07 3063 643 M00006600A:E07 MA241:B01 3064 661 M00006690A:F06 MA241:C07 3065 739 M00023325D:A08 MA37:B02 3066 742 M00026921D:F12 MA40:C02 3067 743 M00023325D:F06 MA37:D02 3068 750 M00026924A:E09 MA40:G02 3069 823 M00007940C:A04 MA27:D08 3070 827 M00007941C:H03 MA27:F08 3071 828 M00021638B:F03 MA31:F08 3072 831 M00007941D:C04 MA27:H08 3073 842 M00004054D:D02 3074 857 M00001507A:A10 MA23:E08 3075 858 M00004198D:A01 3076 861 M00001528C:B08 MA23:G08 3077 868 M00008002C:A05 MA29:B03 3078 880 M00008006C:H05 MA29:H03 3079 898 M00026850C:A01 MA39:A02 3080 908 M00026853D:C07 MA39:F02 3081 920 M00026896A:C09 MA39:D08 3082 934 M00001391B:D02 MA15:C02 3083 938 M00001391B:H05 MA15:E02 3084 940 M00001391D:C07 MA15:F02 3085 942 M00001392B:B01 MA15:G02 3086 954 M00001407B:C03 MA15:E08 3087 1011 M00005635B:E02 MA242:B08 3088 1017 M00005636B:B06 MA242:E08 3089 1018 M00006971A:E06 MA240:E08 3090 1019 M00005636D:B08 MA242:F08 3091 1107 M00023302C:A04 MA36:B08 3092 1117 M00023305A:C02 MA36:G08 3093 1172 M00022180A:E08 MA35:B08 3094 1178 M00022181C:H11 MA35:E08 3095 1193 M00001673A:C11 3096 1201 M00003853B:C07 3097 1204 M00022106B:D04 MA34:B08 3098 1209 M00003858B:G01 MA24:E08 3099 1214 M00022109B:A11 MA34:G08 3100 1260 M00022921A:H05 MA22:F02 3101 1282 M00001430D:H07 MA16:A02 3102 1283 M00001360D:H10 MA14:B02 3103 1284 M00001431A:E01 MA16:B02 3104 1285 M00001361A:A02 MA14:C02 3105 1295 M00001362A:B03 MA14:H02 3106 1297 M00001376C:C01 MA14:A08 3107 1300 M00001449A:D02 MA16:B08 3108 1301 M00001378B:A02 MA14:C08 3109 1302 M00001450A:D12 MA16:C08 3110 1303 M00001378C:D08 MA14:D08 3111 1310 M00001451D:F01 MA16:G08 3112 1349 M00006628B:A02 MA241:C02 3113 1444 M00026926C:F03 MA40:B03 3114 1458 M00026963B:H03 MA40:A09 3115 1464 M00026964A:E10 MA40:D09 3116 1468 M00026965C:A11 MA40:F09 3117 1493 M00001398A:D11 MA244:C09 3118 1512 M00008095C:H08 MA31:D03 3119 1523 M00007942A:F12 MA27:B09 3120 1554 M00004212B:B12 MA25:A09 3121 1576 M00008014C:E11 MA29:D05 3122 1578 M00008015A:B05 MA29:E05 3123 1586 M00022049A:B08 MA33:A05 3124 1602 M00026856B:F08 MA39:A03 3125 1604 M00026856C:H12 MA39:B03 3126 1628 M00026900D:A03 MA39:F09 3127 1630 M00026900D:C12 MA39:G09 3128 1632 M00026901D:A03 MA39:H09 3129 1642 M00001393A:G03 MA15:E03 3130 1656 M00001409B:D03 MA15:D09 3131 1658 M00001409B:G01 MA15:E09 3132 1660 M00001410C:C09 MA15:F09 3133 1662 M00001410D:A03 MA15:G09 3134 1697 M00005504D:F06 MA242:A03 3135 1709 M00005510D:H10 MA242:G03 3136 1726 M00006990D:D06 MA240:G09 3137 1761 SL146 MA248:A03 3138 1775 SL153 MA248:H03 3139 1785 SL198 MA248:E09 3140 1787 SL199 MA248:F09 3141 1789 SL200 MA248:G09 3142 1797 M00023283D:C03 MA36:C03 3143 1799 M00023283D:D03 MA36:D03 3144 1801 M00023284A:D09 MA36:E03 3145 1807 M00023285D:C05 MA36:H03 3146 1809 M00023306C:H11 MA36:A09 3147 1813 M00023308D:B06 MA36:C09 3148 1817 M00023309D:H04 MA36:E09 3149 1819 M00023310A:D07 MA36:F09 3150 1875 M00008079C:H04 MA30:B09 3151 1883 M00008080B:B10 MA30:F09 3152 1884 M00022198D:C02 MA35:F09 3153 1886 M00022198D:G03 MA35:G09 3154 1895 M00003768B:B09 MA24:D03 3155 1910 M00022110C:A08 MA34:C09 3156 1913 M00003886C:H08 MA24:E09 3157 1960 M00023297B:A10 MA22:D03 3158 1966 M00023314C:G05 MA22:G03 3159 1991 M00001363B:C04 MA14:D03 3160 1992 M00001434D:F08 MA16:D03 3161 1994 M00001435B:A04 MA16:E03 3162 1996 M00001435B:B09 MA16:F03 3163 2000 M00001435C:F08 MA16:H03 3164 2001 M00001381A:F03 MA14:A09 3165 2004 M00001453B:E11 MA16:B09 3166 2008 M00001453C:D02 MA16:D09 3167 2050 M00007121D:A05 MA243:A03 3168 2052 M00007122C:F03 MA243:B03 3169 2053 M00006638A:G02 MA241:C03 3170 2059 M00006639B:H09 MA241:F03 3171 2064 M00007127C:C11 MA243:H03 3172 2073 M00006720D:C11 MA241:E09 3173 2075 M00006728C:E07 MA241:F09 3174 2156 M00026931D:E08 MA40:F04 3175 2158 M00026932D:B08 MA40:G04 3176 2168 M00026969D:D02 MA40:D10 3177 2169 M00023393B:E02 MA37:E10 3178 2185 M00003782D:D06 MA244:E04 3179 2189 M00004105D:B04 MA244:G04 3180 2199 M00001556D:B11 MA244:D10 3181 2234 M00021664B:G03 MA31:E10 3182 2242 M00004078A:A07 3183 2263 M00001561A:B03 MA23:D10 3184 2284 M00008023C:A06 MA29:F07 3185 2286 M00008024C:F02 MA29:G07 3186 2288 M00008024C:G06 MA29:H07 3187 2292 M00022057C:H10 MA33:B07 3188 2294 M00022059B:B06 MA33:C07 3189 2324 M00026902B:F10 MA39:B10 3190 2342 M00001394D:B08 MA15:C04 3191 2354 M00001415A:G05 MA15:A10 3192 2356 M00001416B:E03 MA15:B10 3193 2368 M00001421B:B12 MA15:H10 3194 2413 M00005528C:E02 MA242:G04 3195 2513 M00023312D:F10 MA36:A10 3196 2566 M00022157A:C06 MA35:C04 3197 2576 M00022165A:A11 MA35:H04 3198 2584 M00022206A:B10 MA35:D10 3199 2601 M00003811B:F09 3200 2605 M00003812D:A11 3201 2606 M00022088D:C10 MA34:G04 3202 2613 M00003910B:C12 3203 2689 M00001366A:F06 MA14:A04 3204 2692 M00001435C:F12 MA16:B04 3205 2694 M00001436B:E11 MA16:C04 3206 2695 M00001366B:E01 MA14:D04 3207 2696 M00001436C:C03 MA16:D04 3208 2700 M00001437A:B01 MA16:F04 3209 2702 M00001437B:B08 MA16:G04 3210 2712 M00001467B:H05 3211 2716 M00001468A:D02 MA16:F10 3212 2756 M00007131B:B11 MA243:B04 3213 2761 M00006650A:A10 MA241:E04 3214 2765 M00006653C:B09 MA241:G04 3215 2766 M00007154B:H08 MA243:G04 3216 2769 M00006740A:E02 MA241:A10 3217 2770 M00021621A:D04 MA243:A10 3218 2771 M00006740B:F11 MA241:B10 3219 2773 M00006741C:A01 MA241:C10 3220 2780 M00022171C:A04 MA243:F10 3221 2858 M00026937C:B08 MA40:E05 3222 2861 M00023367A:H06 MA37:G05 3223 2876 M00026985C:E12 MA40:F11 3224 2916 M00008100A:A07 MA31:B05 3225 2921 M00007936B:H07 MA27:E05 3226 2924 M00008100C:E05 MA31:F05 3227 2937 M00007947B:B02 MA27:E11 3228 2956 M00004105A:C09 MA25:F05 3229 2957 M00001433C:D09 MA23:G05 3230 2980 M00008027B:D09 MA29:B09 3231 2984 M00008028D:B01 MA29:D09 3232 2988 M00008039A:C09 MA29:F09 3233 3026 M00026905A:A10 MA39:A11 3234 3030 M00026905D:C05 MA39:C11 3235 3054 M00001401B:A06 MA15:G05 3236 3056 M00001402A:A08 MA15:H05 3237 3105 M00005534C:E12 MA242:A05 3238 3111 M00005542A:D09 MA242:D05 3239 3132 M00007031D:E02 MA240:F11 3240 3134 M00007032A:D04 MA240:G11 3241 3135 M00005813C:F12 MA242:H11 3242 3171 SL163 MA248:B05 3243 3173 SL164 MA248:C05 3244 3179 SL167 MA248:F05 3245 3181 SL168 MA248:G05 3246 3183 SL169 MA248:H05 3247 3231 M00023320B:A03 MA36:H11 3248 3238 M00005350B:F10 MA246:C05 3249 3267 M00008069D:F01 MA30:B05 3250 3268 M00022165B:C08 MA35:B05 3251 3272 M00022165C:E12 MA35:D05 3252 3274 M00022166C:E07 MA35:E05 3253 3275 M00008072D:E12 MA30:F05 3254 3282 M00022211B:D05 MA35:A11 3255 3293 M00008089A:E09 MA30:G11 3256 3317 M00003974D:E04 MA24:C11 3257 3323 M00003980D:F10 MA24:F11 3258 3327 M00003984D:C08 MA24:H11 3259 3370 M00023373D:A01 MA22:E05 3260 3376 M00023396D:D01 MA22:H05 3261 3394 M00001437D:E12 MA16:A05 3262 3396 M00001438A:B09 MA16:B05 3263 3401 M00001369A:C07 MA14:E05 3264 3404 M00001439C:A07 MA16:F05 3265 3407 M00001369C:A05 MA14:H05 3266 3410 M00001468D:B11 MA16:A11 3267 3411 M00001386B:F08 MA14:B11 3268 3419 M00001387A:A08 MA14:F11 3269 3460 M00007163A:B10 MA243:B05 3270 3465 M00006675C:A06 MA241:E05 3271 3470 M00007191C:A06 MA243:G05 3272 3471 M00006678A:D02 MA241:H05 3273 3562 M00026941C:A12 MA40:E06 3274 3578 M00026996A:E01 MA40:E12 3275 3581 M00023401B:E06 MA37:G12 3276 3584 M00027005B:D03 MA40:H12 3277 3621 M00007937B:A02 MA27:C06 3278 3622 M00021612C:E11 MA31:C06 3279 3629 M00007938C:C12 MA27:G06 3280 3675 M00001623C:A06 MA23:F12 3281 3677 M00001630D:A11 MA23:G12 3282 3682 M00008044B:E11 MA29:A11 3283 3684 M00008044C:C10 MA29:B11 3284 3686 M00008044D:B08 MA29:C11 3285 3688 M00008044D:C05 MA29:D11 3286 3706 M00022074C:A04 MA33:E11 3287 3738 M00026910C:D12 MA39:E12 3288 3742 M00026913A:D06 MA39:G12 3289 3752 M00001402C:H08 MA15:D06 3290 3756 M00001404C:C11 MA15:F06 3291 3813 M00005587B:G05 MA242:C06 3292 3814 M00006934D:D10 MA240:C06 3293 3885 SL176 MA248:G06 3294 3905 M00023295D:E05 MA36:A06 3295 3921 M00023320B:C02 MA36:A12 3296 3956 M00005401B:F12 MA246:B12 3297 3979 M00008074D:C05 MA30:F06 3298 3982 M00022175B:F06 MA35:G06 3299 3998 M00022230B:C10 MA35:G12 3300 4006 M00022093C:C08 MA34:C06 3301 4008 M00022093C:C12 MA34:D06 3302 4028 M00022132A:H07 MA34:F12 3303 4066 M00023397B:D04 MA22:A06 3304 4074 M00023399D:G04 MA22:E06 3305 4098 M00001439D:C09 MA16:A06 3306 4100 M00001441A:A09 MA16:B06 3307 4101 M00001369D:E02 MA14:C06 3308 4105 M00001371D:H10 MA14:E06 3309 4107 M00001372A:D01 MA14:F06 3310 4110 M00001444C:F03 MA16:G06 3311 4112 M00001445A:B02 3312 4119 M00001388D:F11 MA14:D12 3313 4124 M00001481C:A12 MA16:F12 3314 4125 M00001389B:B05 MA14:G12 3315 4127 M00001389C:G01 MA14:H12 3316 4128 M00001482D:D11 MA16:H12 3317 4183 M00006809B:F04 MA241:D12 3318 8513 I:3325119:07A01:A01 MA127:A01 3319 8517 I:3033345:07A01:C01 MA127:C01 3320 8537 I:3176222:07A01:E07 MA127:E07 3321 8542 I:2510627:07B01:G07 MA129:G07 3322 8546 I:1705208:06B01:A01 MA125:A01 3323 8566 I:1672781:06B01:C07 MA125:C07 3324 8568 I:1712888:06B01:D07 MA125:D07 3325 8570 I:1696224:06B01:E07 MA125:E07 3326 8576 I:3935034:06B01:H07 MA125:H07 3327 8617 I:1800114:03A01:E01 MA111:E01 3328 8631 I:1976029:03A01:D07 MA111:D07 3329 8634 I:1439934:03B01:E07 MA113:E07 3330 8645 I:2512879:01A01:C01 MA103:C01 3331 8660 I:2900277:01B01:B07 MA105:B07 3332 8661 I:1479255:01A01:C07 MA103:C07 3333 8738 I:2648612:04B01:A01 MA117:A01 3334 8741 I:1889867:04A01:C01 MA115:C01 3335 8743 I:1858905:04A01:D01 MA115:D01 3336 8752 I:2591494:04B01:H01 MA117:H01 3337 8754 I:2916261:04B01:A07 MA117:A07 3338 8756 I:2397815:04B01:B07 MA117:B07 3339 8760 I:2182095:04B01:D07 MA117:D07 3340 8769 I:2506194:02A01:A01 MA107:A01 3341 8773 I:1806219:02A01:C01 MA107:C01 3342 8797 I:1729724:02A01:G07 MA107:G07 3343 8845 I:1886842:05A02:G01 MA120:G01 3344 8851 I:1352669:05A02:B07 MA120:B07 3345 8854 I:1755847:05B02:C07 MA122:C07 3346 8856 I:1803418:05B02:D07 MA122:D07 3347 8860 I:1568725:05B02:F07 MA122:F07 3348 8861 I:1857708:05A02:G07 MA120:G07 3349 8862 I:1687060:05B02:G07 MA122:G07 3350 8881 I:3407289:07A02:A07 MA128:A07 3351 8883 I:1235535:07A02:B07 MA128:B07 3352 8984 I:1525795:03B02:D07 MA114:D07 3353 8991 I:3744592:03A02:H07 MA112:H07 3354 8995 I:1485817:01A02:B01 MA104:B01 3355 8996 I:2365149:01B02:B01 MA106:B01 3356 8999 I:1439677:01A02:D01 MA104:D01 3357 9006 I:2372275:01B02:G01 MA106:G01 3358 9008 I:3211615:01B02:H01 MA106:H01 3359 9012 I:2368282:01B02:B07 MA106:B07 3360 9095 I:1737833:04A02:D01 MA116:D01 3361 9100 I:2382192:04B02:F01 MA118:F01 3362 9111 I:1958902:04A02:D07 MA116:D07 3363 9118 I:1704472:04B02:G07 MA118:G07 3364 9119 I:1903767:04A02:H07 MA116:H07 3365 9125 I:1268080:02A02:C01 MA108:C01 3366 9141 I:1347384:02A02:C07 MA108:C07 3367 9168 I:2344817:08B01:H02 MA133:H02 3368 9171 I:3236109:08A01:B08 MA131:B08 3369 9247 I:2832506:07A01:H08 MA127:H08 3370 9252 I:1673876:06B01:B02 MA125:B02 3371 9258 I:3686211:06B01:E02 MA125:E02 3372 9264 I:2449837:06B01:H02 MA125:H02 3373 9270 I:1613874:06B01:C08 MA125:C08 3374 9317 I:1813409:03A01:C02 MA111:C02 3375 9329 I:1975514:03A01:A08 MA111:A08 3376 9347 I:1403294:01A01:B02 MA103:B02 3377 9352 I:2414624:01B01:D02 MA105:D02 3378 9360 I:2901811:01B01:H02 MA105:H02 3379 9364 I:2683564:01B01:B08 MA105:B08 3380 9366 I:2725511:01B01:C08 MA105:C08 3381 9441 I:1431273:04A01:A02 MA115:A02 3382 9442 I:1636639:04B01:A02 MA117:A02 3383 9448 I:2455617:04B01:D02 MA117:D02 3384 9452 I:2952504:04B01:F02 MA117:F02 3385 9457 I:1483847:04A01:A08 MA115:A08 3386 9460 I:2923150:04B01:B08 MA117:B08 3387 9467 I:1813133:04A01:F08 MA115:F08 3388 9472 I:2510171:04B01:H08 MA117:H08 3389 9487 I:2190284:02A01:H02 MA107:H02 3390 9540 I:1522716:05B02:B02 MA122:B02 3391 9549 I:1901271:05A02:G02 MA120:G02 3392 9552 I:1820522:05B02:H02 MA122:H02 3393 9553 I:2365295:05A02:A08 MA120:A08 3394 9557 I:1335140:05A02:C08 MA120:C08 3395 9560 I:1822577:05B02:D08 MA122:D08 3396 9618 I:1306814:06B02:A08 MA126:A08 3397 9624 I:3034694:06B02:D08 MA126:D08 3398 9666 I:1453049:03B02:A02 MA114:A02 3399 9672 I:1453748:03B02:D02 MA114:D02 3400 9677 I:3001492:03A02:G02 MA112:G02 3401 9685 I:3876715:03A02:C08 MA112:C08 3402 9687 I:2992851:03A02:D08 MA112:D08 3403 9694 I:1500649:03B02:G08 MA114:G08 3404 9699 I:1512943:01A02:B02 MA104:B02 3405 9703 I:1467565:01A02:D02 MA104:D02 3406 9720 I:2455118:01B02:D08 MA106:D08 3407 9722 I:2840251:01B02:E08 MA106:E08 3408 9770 I:2911347:10B02:E02 MA67:E02 3409 9790 I:1812030:10B02:G08 MA67:G08 3410 9820 I:2663606:04B02:F08 MA118:F08 3411 9833 I:1308333:02A02:E02 MA108:E02 3412 9834 I:1578941:02B02:E02 MA110:E02 3413 9847 I:1535439:02A02:D08 MA108:D08 3414 9856 I:1857475:02B02:H08 MA110:H08 3415 9884 I:2908878:08B01:F09 MA133:F09 3416 9925 I:2830575:07A01:C03 MA127:C03 3417 9934 I:1557906:07B01:G03 MA129:G03 3418 9964 I:2200604:06B01:F03 MA125:F03 3419 9973 I:1653326:06A01:C09 MA123:C09 3420 9981 I:1720149:06A01:G09 MA123:G09 3421 10030 I:1560987:03B01:G03 MA113:G03 3422 10046 I:1510714:03B01:G09 MA113:G09 3423 10050 I:2501484:01B01:A03 MA105:A03 3424 10051 I:1379063:01A01:B03 MA103:B03 3425 10054 I:2797902:01B01:C03 MA105:C03 3426 10062 I:1805613:01B01:G03 MA105:G03 3427 10063 I:1524885:01A01:H03 MA103:H03 3428 10064 I:2888464:01B01:H03 MA105:H03 3429 10148 I:1992788:04B01:B03 MA117:B03 3430 10155 I:1413451:04A01:F03 MA115:F03 3431 10166 I:2779515:04B01:C09 MA117:C09 3432 10206 I:1583076:02B01:G09 MA109:G09 3433 10243 I:3070110:05A02:B03 MA120:B03 3434 10255 I:1904493:05A02:H03 MA120:H03 3435 10257 I:2860815:05A02:A09 MA120:A09 3436 10285 I:1930135:07A02:G03 MA128:G03 3437 10318 I:3747901:06B02:G03 MA126:G03 3438 10321 I:1720946:06A02:A09 MA124:A09 3439 10328 I:2877413:06B02:D09 MA126:D09 3440 10330 I:3035279:06B02:E09 MA126:E09 3441 10393 I:2503913:03A02:E09 MA112:E09 3442 10403 I:1517380:01A02:B03 MA104:B03 3443 10406 I:3138128:01B02:C03 MA106:C03 3444 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MA174:H05 4146 24151 M00056611C:D03 MA174:D11 4147 24155 M00056611D:B03 MA174:F11 4148 24157 M00056611D:F08 MA174:G11 4149 24159 M00056614C:F06 MA174:H11 4150 24161 RG:358387:10009:A05 MA158:A05 4151 24193 M00057302A:F08 MA182:A05 4152 24197 M00057302C:H09 MA182:C05 4153 24204 M00054496A:B09 MA184:F05 4154 24208 M00054496A:H05 MA184:H05 4155 24209 M00042460B:A08 MA182:A11 4156 24210 M00054524B:B09 MA184:A11 4157 24212 M00054526C:E05 MA184:B11 4158 24213 M00042516B:A08 MA182:C11 4159 24215 M00042517D:H10 MA182:D11 4160 24216 M00054527B:H11 MA184:D11 4161 24217 M00042517D:H11 MA182:E11 4162 24222 M00054529C:G04 MA184:G11 4163 24223 M00043300D:A06 MA182:H11 4164 24230 M00054958A:G10 MA198:C05 4165 24232 M00054958B:B07 MA198:D05 4166 24240 M00054961D:E08 MA198:H05 4167 24246 M00055015C:H02 MA198:C11 4168 24250 M00055016B:D03 MA198:E11 4169 24265 M00055764D:D05 MA170:E05 4170 24275 M00055815C:E08 MA170:B11 4171 24283 M00055819B:B12 MA170:F11 4172 24287 M00055820C:H11 MA170:H11 4173 24289 M00055204B:C04 MA196:A05 4174 24295 M00055209A:C09 MA196:D05 4175 24311 M00055252C:G12 MA196:D11 4176 24354 M00056934C:D08 MA177:A05 4177 24355 M00055989C:D03 MA179:B05 4178 24360 M00056937C:G12 MA177:D05 4179 24367 M00055997B:A02 MA179:H05 4180 24373 M00056087A:G01 MA179:C11 4181 24375 M00056091A:H05 MA179:D11 4182 24378 M00056966B:A05 MA177:E11 4183 24379 M00056093A:F08 MA179:F11 4184 24383 M00056096C:H10 MA179:H11 4185 24399 M00054766B:E10 MA188:H05 4186 24403 M00054817B:H09 MA188:B11 4187 24407 M00054818D:G04 MA188:D11 4188 24450 M00042851D:H04 MA172:A05 4189 24452 M00042853A:F01 MA172:B05 4190 24457 M00055426A:G06 MA168:E05 4191 24467 M00055496A:G12 MA168:B11 4192 24475 M00055509C:C02 MA168:F11 4193 24477 M00055510B:F08 MA168:G11 4194 24479 M00055510D:A08 MA168:H11 4195 24483 M00056748C:B08 MA175:B05 4196 24485 M00056749A:F01 MA175:C05 4197 24493 M00056754B:A10 MA175:G05 4198 24495 M00056754B:H06 MA175:H05 4199 24521 RG:1653390:10014:E05 MA163:E05 4200 24525 RG:1669553:10014:G05 MA163:G05 4201 24547 M00043355A:H12 MA183:B05 4202 24549 M00043355B:F10 MA183:C05 4203 24557 M00043357B:B10 MA183:G05 4204 24558 M00054557C:D09 MA185:G05 4205 24559 M00043358B:G11 MA183:H05 4206 24561 M00043396D:B04 MA183:A11 4207 24576 M00054612D:D11 MA185:H11 4208 24578 M00055409B:D08 MA199:A05 4209 24580 M00055409D:F06 MA199:B05 4210 24582 M00055410A:A06 MA199:C05 4211 24587 M00056659A:D08 MA186:F05 4212 24599 M00056704C:H08 MA186:D11 4213 24609 M00055553C:B06 MA169:A06 4214 24610 M00056280B:D10 MA181:A06 4215 24614 M00056282D:G10 MA181:C06 4216 24622 M00056288B:A12 MA181:G06 4217 24627 M00055686D:E11 MA169:B12 4218 24630 M00042346B:F09 MA181:C12 4219 24633 M00055698C:E05 MA169:E12 4220 24634 M00042347C:D07 MA181:E12 4221 24635 M00055702C:C04 MA169:F12 4222 24638 M00042348C:F03 MA181:G12 4223 24648 M00055335D:E01 MA197:D06 4224 24708 M00056180C:E06 MA180:B06 4225 24712 M00056184B:G11 MA180:D06 4226 24721 M00056514A:F06 MA173:A12 4227 24727 M00056514C:H11 MA173:D12 4228 24741 M00054674D:C05 MA187:C06 4229 24743 M00054675A:H07 MA187:D06 4230 24744 M00054878A:G12 MA189:D06 4231 24751 M00054676B:D07 MA187:H06 4232 24755 M00054725A:E09 MA187:B12 4233 24758 M00054924C:B09 MA189:C12 4234 24759 M00054726D:B04 MA187:D12 4235 24762 M00054927A:H09 MA189:E12 4236 24763 M00054727C:F11 MA187:F12 4237 24767 M00054728A:H05 MA187:H12 4238 24768 M00054930B:G05 MA189:H12 4239 24772 M00057214C:G11 MA193:B06 4240 24776 M00057216C:G01 MA193:D06 4241 24780 M00057217C:B07 MA193:F06 4242 24803 M00042695A:H04 MA167:B06 4243 24805 M00042695D:D09 MA167:C06 4244 24808 M00042771A:D01 MA171:D06 4245 24810 M00042772D:F02 MA171:E06 4246 24812 M00042773A:A12 MA171:F06 4247 24813 M00042699B:B10 MA167:G06 4248 24817 M00042889A:H07 MA167:A12 4249 24818 M00042819A:C09 MA171:A12 4250 24820 M00042819C:B03 MA171:B12 4251 24821 M00042895B:C02 MA167:C12 4252 24822 M00042823B:A02 MA171:C12 4253 24825 M00042895D:B04 MA167:E12 4254 24843 M00056564B:F11 MA174:F06 4255 24845 M00056564C:E08 MA174:G06 4256 24849 M00056615D:A01 MA174:A12 4257 24861 M00056620D:F02 MA174:G12 4258 24865 RG:359184:10009:A06 MA158:A06 4259 24887 RG:428530:10009:D12 MA158:D12 4260 24897 M00057310A:A07 MA182:A06 4261 24908 M00054503C:H10 MA184:F06 4262 24917 M00043302C:D03 MA182:C12 4263 24924 M00054535B:F10 MA184:F12 4264 24926 M00054535C:D10 MA184:G12 4265 24928 M00054535C:H09 MA184:H12 4266 24934 M00054964B:A08 MA198:C06 4267 24936 M00054966C:H01 MA198:D06 4268 24952 M00055022D:F01 MA198:D12 4269 24958 M00055026C:C12 MA198:G12 4270 24960 M00055027B:C11 MA198:H12 4271 24985 M00055826D:C11 MA170:E12 4272 24989 M00055828C:D10 MA170:G12 4273 24991 M00055828D:F12 MA170:H12 4274 24995 M00055215C:E11 MA196:B06 4275 24999 M00055217C:E09 MA196:D06 4276 25001 M00055221B:C01 MA196:E06 4277 25005 M00055222A:E02 MA196:G06 4278 25012 M00056226D:F03 MA180:B12 4279 25019 M00055258A:G02 MA196:F12 4280 25057 M00055998A:A02 MA179:A06 4281 25058 M00056945A:B11 MA177:A06 4282 25062 M00056945D:H03 MA177:C06 4283 25063 M00056001A:F11 MA179:D06 4284 25068 M00056946D:B04 MA177:F06 4285 25073 M00056101B:B02 MA179:A12 4286 25081 M00056110C:D09 MA179:E12 4287 25083 M00056111B:H03 MA179:F12 4288 25101 M00054772B:H06 MA188:G06 4289 25109 M00054825B:B05 MA188:C12 4290 25111 M00054831A:G04 MA188:D12 4291 25115 M00054831D:B07 MA188:F12 4292 25156 M00042862D:A12 MA172:B06 4293 25162 M00042864A:E05 MA172:E06 4294 25164 M00042864D:E06 MA172:F06 4295 25177 M00055514B:A05 MA168:E12 4296 25191 M00056763B:A12 MA175:D06 4297 25195 M00056767D:F06 MA175:F06 4298 25201 M00056821A:D08 MA175:A12 4299 25205 M00056822C:G03 MA175:C12 4300 25209 M00056823D:H02 MA175:E12 4301 25217 RG:1609994:10014:A06 MA163:A06 4302 25243 RG:1667183:10014:F12 MA163:F12 4303 25249 M00043358D:C06 MA183:A06 4304 25250 M00054558B:E05 MA185:A06 4305 25257 M00043361B:G03 MA183:E06 4306 25277 M00043408C:D11 MA183:G12 4307 25280 M00054632A:E11 MA185:H12 4308 25281 M00056661A:G05 MA186:A06 4309 25283 M00056661C:C11 MA186:B06 4310 25284 M00055412D:E05 MA199:B06 4311 25286 M00055413A:G12 MA199:C06 4312 25288 M00055414D:A09 MA199:D06 4313 25301 M00056707B:C01 MA186:C12 4314 25317 M00056237D:C10 MA181:D01 4315 25319 M00056238B:D03 MA181:E01 4316 25323 M00056239B:D05 MA181:G01 4317 25325 M00056241B:H07 MA181:H01 4318 25380 I:2921194:04B02:C06 MA118:C06 4319 25388 I:1624865:04B02:G06 MA118:G06 4320 25389 I:1728607:04A02:H06 MA116:H06 4321 25390 I:2827453:04B02:H06 MA118:H06 4322 25398 I:2070593:04B02:D12 MA118:D12 4323 25405 I:2683114:04A02:H12 MA116:H12 4324 25419 I:1809336:02A02:G06 MA108:G06

Characterization of Sequences

The sequences of the isolated polynucleotides were first masked to eliminate low complexity sequences using the RepeatMasker masking program, publicly available through a web site supported by the University of Washington (See also Smit, A. F. A. and Green, P., unpublished results). Generally, masking does not influence the final search results, except to eliminate sequences of relatively little interest due to their low complexity, and to eliminate multiple “hits” based on similarity to repetitive regions common to multiple sequences, e.g., Alu repeats. Masking resulted in the elimination of several sequences.

The remaining sequences of the isolated polynucleotides were used in a homology search of the GenBank database using the TeraBLAST program (TimeLogic, Crystal Bay, Nevada), a DNA and protein sequence homology searching algorithm. TeraBLAST is a version of the publicly available BLAST search algorithm developed by the National Center for Biotechnology, modified to operate at an accelerated speed with increased sensitivity on a specialized computer hardware platform. The program was run with the default parameters recommended by TimeLogic to provide the best sensitivity and speed for searching DNA and protein sequences. Gene assignment for the query sequences was determined based on best hit form the GenBank database; expectancy values are provided with the hit.

Summary of TeraBLAST Search Results

Table 30 provides information about the gene corresponding to each polynucleotide. Table 3 includes: (1) the “SEQ ID NO” of the sequence; (2) the “Clone ID” assigned to the clone from which the sequence was isolated; (3) the “MAClone ID” assigned to the clone from which the sequence was isolated; (4) the percentage of masking of the sequence (“Mask Prcnt”) (5) the GenBank Accession Number of the publicly available sequence corresponding to the polynucleotide (“GBHit”); (6) a description of the GenBank sequence (“GBDescription”); and (7) the score of the similarity of the polynucleotide sequence and the GenBank sequence (“GBScore”). The published information for each GenBank and EST description, as well as the corresponding sequence identified by the provided accession number, are incorporated herein by reference. TABLE 30 SEQ ID MAClone Mask NO Clone ID ID Prcnt GBHit GBDescription GBScore 3022 M00026919B:A10 MA40:F01 Z69708 gi|1204106|emb|Z69708.1HSL241B9C 2.2E−208 Human DNA sequence from cosmid L241B9, Huntington's Disease Region, chromosome 4p16.3 contains pol 3023 M00026919B:E07 MA40:G01 Y16675 gi|3378616|emb|Y16675.1HSCPRM1 0 Homo sapiens mRNA for aflatoxin B1- aldehyde reductase 3024 M00026919D:F04 MA40:H01 M62810 gi|188563|gb|M62810.1HUMMITF1   1E−300 Human mitochondrial transcription factor 1 mRNA, complete cds 3025 M00026914D:G06 MA40:A01 NM_020990 gi|11641403|ref|NM_020990.2 Homo 2.3E−288 sapiens creatine kinase, mitochondrial 1 (ubiquitous) (CKMT1), nuclear gene encoding mitochondrial 3026 M00026950A:A09 MA40:D07 BC010020 gi|14603100|gb|BC010020.1BC010020 9.3E−207 Homo sapiens, adaptor-related protein complex 3, sigma 2 subunit, clone MGC: 19643 IMAGE: 2959670, 3027 M00003820C:A09 MA244:B01 0.83544 AK026527 gi|10439404|dbj|AK026527.1AK026527 6.6E−24 Homo sapiens cDNA: FLJ22874 fis, clone KAT02871 3028 M00001673A:G03 MA244:E01 BC018192 gi|17390428|gb|BC018192.1BC018192 4.6E−274 Homo sapiens, inositol 1,3,4-triphosphate 5/6 kinase, clone MGC: 21491 IMAGE: 3867269, mRNA, comple 3029 M00007939A:A12 MA27:B07 3030 M00007939A:B11 MA27:D07 AK055664 gi|16550447|dbj|AK055664.1AK055664 6.7E−186 Homo sapiens cDNA FLJ31102 fis, clone IMR322000010 3031 M00007939B:G03 MA27:H07 BC006230 gi|13623260|gb|BC006230.1BC006230 2.3E−151 Homo sapiens, lysophospholipase-like, clone MGC: 10338 IMAGE: 3945191, mRNA, complete cds 3032 M00007997D:G08 MA29:C01 BC012323 gi|15147375|gb|BC012323.1BC012323 2.1E−198 Homo sapiens, Similar to cut (Drosophila)- like 1 (CCAAT displacement protein), clone IMAGE: 455060 3033 M00026894C:E11 MA39:F07 AF052955 gi|8117711|gb|AF052955.1AF052955   9E−204 Homo sapiens F1-ATPase epsilon-subunit (ATP5E) mRNA, complete cds; nuclear gene for mitochondrial 3034 M00001391A:C05 MA15:G01 AK000140 gi|7020034|dbj|AK000140.1AK000140 2.2E−107 Homo sapiens cDNA FLJ20133 fis, clone COL06539 3035 M00006818A:A06 MA240:C01 0.06554 AL136706 gi|12052931|emb|AL136706.1HSM801674 9.2E−248 Homo sapiens mRNA; cDNA DKFZp566B2024 (from clone DKFZp566B2024); complete cds 3036 M00023278A:F09 MA36:E01 3037 M00023299A:G01 MA36:C07 3038 M00023301A:A11 MA36:F07 BC007270 gi|13938284|gb|BC007270.1BC007270   1E−300 Homo sapiens, clone MGC: 15585 IMAGE: 3160319, mRNA, complete cds 3039 M00008050A:D12 MA30:C01 BC015839 gi|16198382|gb|BC015839.1BC015839 1.6E−267 Homo sapiens, clone IMAGE: 4296901, mRNA 3040 M00022135A:C04 MA35:F01 BC007925 gi|14043985|gb|BC007925.1BC007925 1.3E−124 Homo sapiens, retinoid X receptor, alpha, clone MGC: 14451 IMAGE: 4304205, mRNA, complete cds 3041 M00022137A:A05 MA35:G01 AK025549 gi|10438098|dbj|AK025549.1AK025549 1.6E−267 Homo sapiens cDNA: FLJ21896 fis, clone HEP03441 3042 M00022176C:A07 MA35:A07 BC000393 gi|12653248|gb|BC000393.1BC000393 2.4E−183 Homo sapiens, Similar to CAAX box 1, clone MGC: 8471 IMAGE: 2821721, mRNA, complete cds 3043 M00008077B:A08 MA30:D07 U09564 gi|507212|gb|U09564.1HSU09564 Human 6.3E−211 serine kinase mRNA, complete cds 3044 M00008077C:D09 MA30:G07 U50939 gi|1314559|gb|U50939.1HSU50939 1.4E−258 Human amyloid precursor protein-binding protein 1 mRNA, complete cds 3045 M00022081C:E09 MA34:F01 AJ271408 gi|6729589|emb|AJ271408.1HSA271408   1E−237 Homo sapiens mRNA for Fas-associated factor, FAF1 (Faf1 gene) 3046 M00001662A:G06 MA24:H01 BC006229 gi|13623258|gb|BC006229.1BC006229 1.6E−264 Homo sapiens, cytochrome c oxidase subunit Vb, clone MGC: 10622 IMAGE: 3952882, mRNA, complete cds 3047 M00022102B:B11 MA34:D07 AJ250229 gi|8926686|emb|AJ250229.1HSA250229 0 Homo sapiens mRNA for chromosome 11 hypothetical protein (ORF1) 3048 M00022102B:E08 MA34:E07 3049 M00022569D:G06 MA22:F01 0.0572 U08839 gi|517197|gb|U08839.1HSU08839 Human 6.7E−233 urokinase-type plasminogen activator receptor mRNA, complete cds 3050 M00001358B:B11 MA14:A01 AB047848 gi|11094286|dbj|AB047848.1AB047848 4.3E−299 Homo sapiens mRNA for zetal-COP, complete cds 3051 M00001429A:G04 MA16:A01 BC000491 gi|12653440|gb|BC000491.1BC000491 0 Homo sapiens, proliferating cell nuclear antigen, clone MGC: 8367 IMAGE: 2820036, mRNA, complete cd 3052 M00001358B:F05 MA14:B01 BC000706 gi|12653834|gb|BC000706.1BC000706 1.1E−299 Homo sapiens, Similar to G8 protein, clone MGC: 1225 IMAGE: 3349773, mRNA, complete cds 3053 M00001429C:C03 MA16:C01 X16064 gi|37495|emb|X16064.1HSTUMP Human 0 mRNA for translationally controlled tumor protein 3054 M00001359D:B04 MA14:E01 AK000481 gi|7020597|dbj|AK000481.1AK000481   1E−300 Homo sapiens cDNA FLJ20474 fis, clone KAT07183 3055 M00001360A:E10 MA14:F01 BC002899 gi|12804092|gb|BC002899.1BC002899 6.4E−267 Homo sapiens, protein (peptidyl-prolyl cis/trans isomerase) NIMA-interacting 1, clone MGC: 10717 I 3056 M00001360C:B05 MA14:G01 NM_001014 gi|13904867|ref|NM_001014.2 Homo 2.1E−282 sapiens ribosomal protein S10 (RPS 10), mRNA 3057 M00001430B:F01 MA16:G01 AL050096 gi|4884121|emb|AL050096.1HSM800178 6.9E−47 Homo sapiens mRNA; cDNA DKFZp586A0419 (from clone DKFZp586A0419); partial cds 3058 M00001430C:A02 MA16:H01 AF083248 gi|5106790|gb|AF083248.1AF083248 0 Homo sapiens ribosomal protein L26 homolog mRNA, complete cds 3059 M00001445C:H05 MA16:A07 X02152 gi|34312|emb|X02152.1HSLDHAR 0 Human mRNA for lactate dehydrogenase- A (LDH-A, EC 1.1.1.27) 3060 M00001445D:D07 MA16:B07 X73458 gi|312997|emb|X73458.1HSPLK1 2.7E−266 H. sapiens plk-1 mRNA 3061 M00001374D:D10 MA14:G07 BC018620 gi|17391359|gb|BC018620.1BC018620 8.3E−254 Homo sapiens, Similar to ADP- ribosyltransferase (NAD+; poly (ADP- ribose) polymerase), clone IMAGE 3062 M00001375A:A08 MA14:H07 AF231705 gi|8745393|gb|AF231705.1AF231705 4.1E−137 Homo sapiens Alu co-repressor 1 (ACR1) mRNA, complete cds 3063 M00006600A:E07 MA241:B01 AK001635 gi|7023008|dbj|AK001635.1AK001635 3.2E−281 Homo sapiens cDNA FLJ10773 fis, clone NT2RP4000246, moderately similar to NPC DERIVED PROLINE RIC 3064 M00006690A:F06 MA241:C07 0.28152 3065 M00023325D:A08 MA37:B02 BC001901 gi|12804898|gb|BC001901.1BC001901 2.7E−294 Homo sapiens, BCL2-antagonist of cell death, clone MGC: 2100 IMAGE: 3537914, mRNA, complete cds 3066 M00026921D:F12 MA40:C02 AK054686 gi|16549280|dbj|AK054686.1AK054686 0 Homo sapiens cDNA FLJ30124 fis, clone BRACE1000093, highly similar to TNF RECEPTOR ASSOCIATED FA 3067 M00023325D:F06 MA37:D02 0.15781 BC017660 gi|17389200|gb|BC017660.1BC017660 1.2E−188 Homo sapiens, clone MGC: 14608 IMAGE: 4049404, mRNA, complete cds 3068 M00026924A:E09 MA40:G02 AL359938 gi|8977893|emb|AL359938.1HSM802719 0 Homo sapiens mRNA; cDNA DKFZp547H236 (from clone DKFZp547H236) 3069 M00007940C:A04 MA27:D08 AF381986 gi|17985445|gb|AF381986.1AF381986 1.6E−264 Homo sapiens haplotype X mitochondrion, complete genome 3070 M00007941C:H03 MA27:F08 U97519 gi|2213812|gb|U97519.1HSU97519 Homo 4.5E−271 sapiens podocalyxin-like protein mRNA, complete cds 3071 M00021638B:F03 MA31:F08 NM_004417 gi|7108342|ref|NM_004417.2 Homo 3.2E−250 sapiens dual specificity phosphatase 1 (DUSP1), mRNA 3072 M00007941D:C04 MA27:H08 AL110202 gi|5817121|emb|AL110202.1HSM800854 2.5E−263 Homo sapiens mRNA; cDNA DKFZp586I2022 (from clone DKFZp586I2022) 3073 M00004054D:D02 0.19296 3074 M00001507A:A10 MA23:E08 AF220656 gi|7107358|gb|AF220656.1AF220656 1.4E−255 Homo sapiens apoptosis-associated nuclear protein PHLDA1 (PHLDA1) mRNA, partial cds 3075 M00004198D:A01 AY007138 gi|9956042|gb|AY007138.1 Homo sapiens 0 clone CDABP0061 mRNA sequence 3076 M00001528C:B08 MA23:G08 AF106066 gi|5353548|gb|AF106066.1AF106066 4.1E−28 Homo sapiens RAD17 pseudogene, complete sequence 3077 M00008002C:A05 MA29:B03 AB023173 gi|4589555|dbj|AB023173.1AB023173 1.6E−292 Homo sapiens mRNA for KIAA0956 protein, partial cds 3078 M00008006C:H05 MA29:H03 AF327923 gi|13241760|gb|AF327923.1AF327923 8.2E−205 Homo sapiens transmembrane protein induced by tumor necrosis factor alpha (TMPIT) mRNA, complete 3079 M00026850C:A01 MA39:A02 AK055812 gi|16550635|dbj|AK055812.1AK055812 8.5E−66 Homo sapiens cDNA FLJ31250 fis, clone KIDNE2005336, weakly similar to Homo sapiens antigen NY-CO 3080 M00026853D:C07 MA39:F02 0.27143 AF212248 gi|13182770|gb|AF212248.1AF212248 1.9E−153 Homo sapiens CDA09 mRNA, complete cds 3081 M00026896A:C09 MA39:D08 AK018953 gi|12858931|dbj|AK018953.1AK018953 3.9E−139 Mus musculus adult male testis cDNA, RIKEN full-length enriched library, clone: 1700111D04, full 3082 M00001391B:D02 MA15:C02 D86956 gi|1503985|dbj|D86956.1D86956 Human 4.7E−221 mRNA for KIAA0201 gene, complete cds 3083 M00001391B:H05 MA15:E02 AL110153 gi|5817055|emb|AL110153.1HSM800798   1E−300 Homo sapiens mRNA; cDNA DKFZp586E0524 (from clone DKFZp586E0524) 3084 M00001391D:C07 MA15:F02 AL136593 gi|7018431|emb|AL136593.1HSM801567 0 Homo sapiens mRNA; cDNA DKFZp761K102 (from clone DKFZp761K102); complete cds 3085 M00001392B:B01 MA15:G02 M73791 gi|189265|gb|M73791.1HUMANOVGENE 3.5E−94 Human novel gene mRNA, complete cds 3086 M00001407B:C03 MA15:E08 BC005116 gi|13477284|gb|BC005116.1BC005116   1E−300 Homo sapiens, structure specific recognition protein 1, clone MGC: 1608 IMAGE: 3536048, mRNA, compl 3087 M00005635B:E02 MA242:B08 0.86798 3088 M00005636B:B06 MA242:E08 AK008041 gi|12841981|dbj|AK008041.1AK008041 1.5E−24 Mus musculus adult male small intestine cDNA, RIKEN full-length enriched library, clone: 2010002G 3089 M00006971A:E06 MA240:E08 NM_002403 gi|9665260|ref|NM_002403.2 Homo 4.7E−274 sapiens microfibrillar-associated protein 2 (MFAP2), transcript variant 2, mRNA 3090 M00005636D:B08 MA242:F08 3091 M00023302C:A04 MA36:B08 AF202922 gi|13540826|gb|AF202922.2AF202922 4.6E−231 Homo sapiens LRP16 (LRP16) mRNA, complete cds 3092 M00023305A:C02 MA36:G08 3093 M00022180A:E08 MA35:B08 BC018918 gi|17511926|gb|BC018918.1BC018918 3.6E−203 Homo sapiens, clone MGC: 12603 IMAGE: 4130906, mRNA, complete cds 3094 M00022181C:H11 MA35:E08 AK001485 gi|7022770|dbj|AK001485.1AK001485 1.6E−161 Homo sapiens cDNA FLJ10623 fis, clone NT2RP2005520, highly similar to Homo sapiens chromosome-ass 3095 M00001673A:C11 U15128 gi|902744|gb|U15128.1HSU15128 Human 0 beta-1,2-N-acetylglucosaminyltransferase II (MGAT2) gene, complete cds 3096 M00003853B:C07 BC008378 gi|14249982|gb|BC008378.1BC008378 2.4E−207 Homo sapiens, programmed cell death 2, clone MGC: 12347 IMAGE: 4102043, mRNA, complete cds 3097 M00022106B:D04 MA34:B08 AB055387 gi|12862374|dbj|AB055387.1AB055387 1.4E−86 Homo sapiens mitochondrial DNA 3098 M00003858B:G01 MA24:E08 0.26044 3099 M00022109B:A11 MA34:G08 AK023237 gi|10435081|dbj|AK023237.1AK023237 0 Homo sapiens cDNA FLJ13175 fis, clone NT2RP3003842 3100 M00022921A:H05 MA22:F02 0.11424 BC002976 gi|12804234|gb|BC002976.1BC002976 0 Homo sapiens, Similar to cytochrome b- 561, clone MGC: 2190 IMAGE: 3535771, mRNA, complete cds 3101 M00001430D:H07 MA16:A02 X58965 gi|35069|emb|X58965.1HSNM23H2G 1.9E−276 H. sapiens RNA for nm23-H2 gene 3102 M00001360D:H10 MA14:B02 NM_002415 gi|4505184|ref|NM_002415.1 Homo 6.2E−158 sapiens macrophage migration inhibitory factor (glycosylation-inhibiting factor) (MIF), mRNA 3103 M00001431A:E01 MA16:B02 AK026534 gi|10439413|dbj|AK026534.1AK026534   1E−300 Homo sapiens cDNA: FLJ22881 fis, clone KAT03571, highly similar to HUMFERL Human ferritin L chai 3104 M00001361A:A02 MA14:C02 NM_004053 gi|15208644|ref|NM_004053.2 Homo 6.7E−270 sapiens bystin-like (BYSL), mRNA 3105 M00001362A:B03 MA14:H02 L47277 gi|986911|gb|L47277.1HUMTOPATRA   1E−296 Homo sapiens (cell line HepG2, HeLa) alpha topoisomerase truncated-form mRNA, 3′UTR 3106 M00001376C:C01 MA14:A08 S73591 gi|688296|gb|S73591.1S73591 Homo 5.8E−233 sapiens brain-expressed HHCPA78 homolog VDUP1 (Gene) mRNA, complete cds 3107 M00001449A:D02 MA16:B08 BC013954 gi|15530314|gb|BC013954.1BC013954 9.6E−291 Homo sapiens, clone IMAGE: 3505920, mRNA 3108 M00001378B:A02 MA14:C08 BC002343 gi|12803082|gb|BC002343.1BC002343 5.2E−124 Homo sapiens, Similar to nucleolin, clone MGC: 8580 IMAGE: 2960982, mRNA, complete cds 3109 M00001450A:D12 MA16:C08 AF106622 gi|4378528|gb|AF106622.1AF106622   5E−280 Homo sapiens mitochondrial inner membrane preprotein translocase Tim17a mRNA, nuclear gene encodin 3110 M00001378C:D08 MA14:D08 0.06114 BC002569 gi|12803486|gb|BC002569.1BC002569   3E−235 Homo sapiens, ribosomal protein S4, X- linked, clone MGC: 2328 IMAGE: 3139352, mRNA, complete cds 3111 M00001451D:F01 MA16:G08 BC001432 gi|12655154|gb|BC001432.1BC001432 0 Homo sapiens, heterogeneous nuclear ribonucleoprotein F, clone MGC: 2197 IMAGE: 3138435, mRNA, comp 3112 M00006628B:A02 MA241:C02 NM_005826 gi|14141188|ref|NM_005826.2 Homo 4.9E−80 sapiens heterogeneous nuclear ribonucleoprotein R (HNRPR), mRNA 3113 M00026926C:F03 MA40:B03 AK027855 gi|14042836|dbj|AK027855.1AK027855 1.1E−215 Homo sapiens cDNA FLJ14949 fis, clone PLACE2000341, highly similar to Homo sapiens sodium-depend 3114 M00026963B:H03 MA40:A09 BC014557 gi|17939595|gb|BC014557.1BC014557 2.6E−241 Homo sapiens, clone IMAGE: 3837222, mRNA 3115 M00026964A:E10 MA40:D09 NM_013375 gi|17572813|ref|NM_013375.2 Homo 1.5E−171 sapiens TATA-binding protein-binding protein (ABT1), mRNA 3116 M00026965C:A11 MA40:F09 0.07092 AK054883 gi|16549505|dbj|AK054883.1AK054883   1E−176 Homo sapiens cDNA FLJ30321 fis, clone BRACE2006281 3117 M00001398A:D11 MA244:C09 BC009503 gi|14550505|gb|BC009503.1BC009503   1E−300 Homo sapiens, G1 to S phase transition 1, clone MGC: 1735 IMAGE: 2822947, mRNA, complete cds 3118 M00008095C:H08 MA31:D03 BC000820 gi|12654032|gb|BC000820.1BC000820 5.3E−255 Homo sapiens, menage a trois 1 (CAK assembly factor), clone MGC: 5154 IMAGE: 3453943, mRNA, complet 3119 M00007942A:F12 MA27:B09 NM_001102 gi|12025669|ref|NM_001102.2 Homo 2.3E−257 sapiens actinin, alpha 1 (ACTN1), mRNA 3120 M00004212B:B12 MA25:A09 0.11538 D38112 gi|644480|dbj|D38112.1HUMMTA Homo 2.4E−48 sapiens mitochondrial DNA, complete sequence 3121 M00008014C:E11 MA29:D05 0.05435 AL080111 gi|5262538|emb|AL080111.1HSM800619 1.7E−292 Homo sapiens mRNA; cDNA DKFZp586G2222 (from clone DKFZp586G2222) 3122 M00008015A:B05 MA29:E05 M23161 gi|339899|gb|M23161.1HUMTRANSC 1.3E−157 Human transposon-like element mRNA 3123 M00022049A:B08 MA33:A05 AK001731 gi|7023175|dbj|AK001731.1AK001731 5.8E−286 Homo sapiens cDNA FLJ10869 fis, clone NT2RP4001677 3124 M00026856B:F08 MA39:A03 AK023351 gi|10435249|dbj|AK023351.1AK023351 1.7E−298 Homo sapiens cDNA FLJ13289 fis, clone OVARC1001170 3125 M00026856C:H12 MA39:B03 0.55489 3126 M00026900D:A03 MA39:F09 NM_000995 gi|16117786|ref|NM_000995.2 Homo 3.5E−200 sapiens ribosomal protein L34 (RPL34), transcript variant 1, mRNA 3127 M00026900D:C12 MA39:G09 BC014377 gi|15680094|gb|BC014377.1BC014377 1.2E−274 Homo sapiens, clone IMAGE: 4041545, mRNA, partial cds 3128 M00026901D:A03 MA39:H09 AK057845 gi|16553806|dbj|AK057845.1AK057845 3.6E−178 Homo sapiens cDNA FLJ25116 fis, clone CBR05731, highly similar to EPHRIN-A1 PRECURSOR 3129 M00001393A:G03 MA15:E03 NM_001015 gi|14277698|ref|NM_001015.2 Homo 0 sapiens ribosomal protein S11 (RPS11), mRNA 3130 M00001409B:D03 MA15:D09 AF104914 gi|4206125|gb|AF104914.1AF104914 0 Homo sapiens map 3p22; 9.65 cR from CHLC.GATA87B02 repeat region, complete sequence 3131 M00001409B:G01 MA15:E09 Z69043 gi|2398656|emb|Z69043.1HSTRAPRNA 3.1E−278 H. sapiens mRNA translocon-associated protein delta subunit precursor 3132 M00001410C:C09 MA15:F09 BC007261 gi|13938270|gb|BC007261.1BC007261 5.3E−252 Homo sapiens, clone MGC: 15545 IMAGE: 3050745, mRNA, complete cds 3133 M00001410D:A03 MA15:G09 X52003 gi|311379|emb|X52003.1HSPS2MKN 3.9E−265 H. sapiens pS2 protein gene 3134 M00005504D:F06 MA242:A03 0.33179 AK026112 gi|10438858|dbj|AK026112.1AK026112   5E−144 Homo sapiens cDNA: FLJ22459 fis, clone HRC10045 3135 M00005510D:H10 MA242:G03 3136 M00006990D:D06 MA240:G09 M79321 gi|187270|gb|M79321.1HUMLYNTK 3.8E−290 Human Lyn B protein mRNA, complete cds 3137 SL146 MA248:A03 0.09302 AF415176 gi|16589066|gb|AF415176.1AF415176 7.8E−92 Homo sapiens CSGEF (SGEF) mRNA, complete cds, alternatively spliced 3138 SL153 MA248:H03 3139 SL198 MA248:E09 0.45185 BC008180 gi|14198240|gb|BC008180.1BC008180 8.2E−115 Homo sapiens, DKFZP586A0522 protein, clone MGC: 5320 IMAGE: 2900478, mRNA, complete cds 3140 SL199 MA248:F09 AF415176 gi|16589066|gb|AF415176.1AF415176 6.2E−92 Homo sapiens CSGEF (SGEF) mRNA, complete cds, alternatively spliced 3141 SL200 MA248:G09 BC005307 gi|13529043|gb|BC005307.1BC005307 3.1E−191 Homo sapiens, kallikrein 3, (prostate specific antigen), clone MGC: 12378 IMAGE: 3950475, mRNA, com 3142 M00023283D:C03 MA36:C03 AF070673 gi|3978241|gb|AF070673.1AF070673 3.7E−181 Homo sapiens stannin mRNA, complete cds 3143 M00023283D:D03 MA36:D03 Z69881 gi|1524091|emb|Z69881.1HSSERCA3M 1.1E−299 H. sapiens mRNA for adenosine triphosphatase, calcium 3144 M00023284A:D09 MA36:E03 AK024338 gi|10436699|dbj|AK024338.1AK024338   1E−300 Homo sapiens cDNA FLJ14276 fis, clone PLACE1005128 3145 M00023285D:C05 MA36:H03 U34877 gi|1143231|gb|U34877.1HSU34877 Homo 6.5E−295 sapiens biliverdin-IX alpha reductase mRNA, complete cds 3146 M00023306C:H11 MA36:A09 BC003366 gi|13097197|gb|BC003366.1BC003366 0 Homo sapiens, calcium-regulated heat- stable protein (24 kD), clone MGC: 5235 IMAGE: 2900952, mRNA, c 3147 M00023308D:B06 MA36:C09 M57730 gi|179320|gb|M57730.1HUMB61 Human 2.1E−176 B61 mRNA, complete cds 3148 M00023309D:H04 MA36:E09 AL136720 gi|12052958|emb|AL136720.1HSM801688 0 Homo sapiens mRNA; cDNA DKFZp566J2046 (from clone DKFZp566J2046); complete cds 3149 M00023310A:D07 MA36:F09 AL359587 gi|8655647|emb|AL359587.1HSM802689 0 Homo sapiens mRNA; cDNA DKFZp762M115 (from clone DKFZp762M115) 3150 M00008079C:H04 MA30:B09 AF201943 gi|9295189|gb|AF201943.1AF201943 5.6E−258 Homo sapiens HAH-P (HAH-P) mRNA, complete cds 3151 M00008080B:B10 MA30:F09 D50683 gi|1827474|dbj|D50683.1D50683 Homo 1.3E−224 sapiens mRNA for TGF-betaIIR alpha, complete cds 3152 M00022198D:C02 MA35:F09 BC001546 gi|16306729|gb|BC001546.1BC001546   1E−300 Homo sapiens, Similar to RIKEN cDNA 1110064N10 gene, clone MGC: 4924 IMAGE: 3462041, mRNA, complete 3153 M00022198D:G03 MA35:G09 X54199 gi|31641|emb|X54199.1HSGAGMR 1.1E−231 Human mRNA for GARS-AIRS-GART 3154 M00003768B:B09 MA24:D03 M32308 gi|202453|gb|M32308.1MUSZFXAA 2.4E−103 Mouse zinc finger protein (Zfx) mRNA, complete cds, clone pDP1115 3155 M00022110C:A08 MA34:C09 AK026894 gi|10439861|dbj|AK026894.1AK026894 9.2E−288 Homo sapiens cDNA: FLJ23241 fis, clone COL01375 3156 M00003886C:H08 MA24:E09 0.36691 AK056001 gi|16550873|dbj|AK056001.1AK056001 7.9E−146 Homo sapiens cDNA FLJ31439 fis, clone NT2NE2000707 3157 M00023297B:A10 MA22:D03 M33376 gi|187444|gb|M33376.1HUMMCDR2 0 Human pseudo-chlordecone reductase mRNA, complete cds 3158 M00023314C:G05 MA22:G03 D87071 gi|1510142|dbj|D87071.1D87071 Human 1.7E−178 mRNA for KIAA0233 gene, complete cds 3159 M00001363B:C04 MA14:D03 AY007220 gi|9945039|gb|AY007220.1 Homo sapiens 1.8E−120 S100-type calcium binding protein A14 mRNA, complete cds 3160 M00001434D:F08 MA16:D03 NM_000852 gi|6552334|ref|NM_000852.2 Homo   1E−300 sapiens glutathione S-transferase pi (GSTP1), mRNA 3161 M00001435B:A04 MA16:E03 X99920 gi|1694827|emb|X99920.1HSS100A13 1.1E−265 H. sapiens mRNA for S100 calcium- binding protein A13 3162 M00001435B:B09 MA16:F03 Y00433 gi|31917|emb|Y00433.1HSGSHPX Human 8.4E−226 mRNA for glutathione peroxidase (EC 1.11.1.9.) 3163 M00001435C:F08 MA16:H03 BC006498 gi|13676331|gb|BC006498.1BC006498   1E−300 Homo sapiens, ribonucleotide reductase M1 polypeptide, clone MGC: 2326 IMAGE: 2989344, mRNA, comple 3164 M00001381A:F03 MA14:A09 BC007590 gi|14043203|gb|BC007590.1BC007590 4.8E−246 Homo sapiens, ribosomal protein, large, P1, clone MGC: 15616 IMAGE: 3343021, mRNA, complete cds 3165 M00001453B:E11 MA16:B09 BC001182 gi|12654686|gb|BC001182.1BC001182   1E−300 Homo sapiens, clone MGC: 2616 IMAGE: 3357266, mRNA, complete cds 3166 M00001453C:D02 MA16:D09 BC007435 gi|13938568|gb|BC007435.1BC007435   1E−300 Homo sapiens, RNA binding motif protein, X chromosome, clone MGC: 4146 IMAGE: 3010123, mRNA, comple 3167 M00007121D:A05 MA243:A03 BC012816 gi|15215444|gb|BC012816.1BC012816   1E−300 Homo sapiens, TGFB-induced factor 2 (TALE family homeobox), clone MGC: 4139 IMAGE: 2964507, mRNA, c 3168 M00007122C:F03 MA243:B03 BC001866 gi|12804840|gb|BC001866.1BC001866 6.4E−227 Homo sapiens, replication factor C (activator 1) 5 (36.5 kD), clone MGC: 1155 IMAGE: 3544137, mRNA, 3169 M00006638A:G02 MA241:C03 J05036 gi|181193|gb|J05036.1HUMCTSE Human 6.7E−153 cathepsin E mRNA, complete cds 3170 M00006639B:H09 MA241:F03 0.36075 BC014188 gi|15559664|gb|BC014188.1BC014188 5.6E−135 Homo sapiens, Similar to golgi autoantigen, golgin subfamily a, 2, clone MGC: 20672 IMAGE: 4644480, 3171 M00007127C:C11 MA243:H03 AB020718 gi|4240310|dbj|AB020718.1AB020718 0 Homo sapiens mRNA for KIAA0911 protein, complete cds 3172 M00006720D:C11 MA241:E09 AF242773 gi|7638246|gb|AF242773.1AF242773 1.2E−218 Homo sapiens mesenchymal stem cell protein DSCD75 mRNA, complete cds 3173 M00006728C:E07 MA241:F09 L05093 gi|401844|gb|L05093.1HUMRIBPROD 0 Homo sapiens ribosomal protein L18a mRNA, complete cds 3174 M00026931D:E08 MA40:F04 AK056187 gi|16551522|dbj|AK056187.1AK056187 2.9E−275 Homo sapiens cDNA FLJ31625 fis, clone NT2RI2003304 3175 M00026932D:B08 MA40:G04 NM_022553 gi|15022812|ref|NM_022553.2 Homo   1E−300 sapiens SAC2 (suppressor of actin mutations 2, yeast, homolog)-like (SACM2L), mRNA 3176 M00026969D:D02 MA40:D10 0.05447 AK027681 gi|14042541|dbj|AK027681.1AK027681 6.5E−159 Homo sapiens cDNA FLJ14775 fis, clone NT2RP4000185 3177 M00023393B:E02 MA37:E10 BC001449 gi|12655184|gb|BC001449.1BC001449 9.4E−157 Homo sapiens, heterogeneous nuclear ribonucleoprotein R, clone MGC: 2039 IMAGE: 3139052, mRNA, comp 3178 M00003782D:D06 MA244:E04 BC000705 gi|12653832|gb|BC000705.1BC000705 1.6E−295 Homo sapiens, clone MGC: 861 IMAGE: 3349507, mRNA, complete cds 3179 M00004105D:B04 MA244:G04 AK056461 gi|16551872|dbj|AK056461.1AK056461   1E−300 Homo sapiens cDNA FLJ31899 fis, clone NT2RP7004173 3180 M00001556D:B11 MA244:D10 0.46689 3181 M00021664B:G03 MA31:E10 0.87158 3182 M00004078A:A07 0.47872 3183 M00001561A:B03 MA23:D10 AF090935 gi|6690235|gb|AF090935.1AF090935 3.4E−256 Homo sapiens clone HQ0569 3184 M00008023C:A06 MA29:F07 U79296 gi|1710278|gb|U79296.1HSU79296 2.2E−257 Human dihydrolipoamide acetyl transferase mRNA, partial cds 3185 M00008024C:F02 MA29:G07 0.26504 AF092737 gi|4741762|gb|AF092737.1AF092737 3.5E−170 Homo sapiens ubiquitously expressed transcript (UXT) mRNA, complete cds 3186 M00008024C:G06 MA29:H07 BC017335 gi|16878274|gb|BC017335.1BC017335   1E−300 Homo sapiens, clone MGC: 29782 IMAGE: 4642600, mRNA, complete cds 3187 M00022057C:H10 MA33:B07 AK027629 gi|14042438|dbj|AK027629.1AK027629 6.8E−79 Homo sapiens cDNA FLJ14723 fis, clone NT2RP3001708, weakly similar to TWISTED GASTRULATION PROTE 3188 M00022059B:B06 MA33:C07 BC005267 gi|14710008|gb|BC005267.1BC005267   1E−300 Homo sapiens, clone IMAGE: 3683864, mRNA 3189 M00026902B:F10 MA39:B10 L15203 gi|402482|gb|L15203.1HUMP1BX Human 4.8E−249 secretory protein (P1.B) mRNA, complete cds 3190 M00001394D:B08 MA15:C04 U58773 gi|6502504|gb|U58773.1HSU58773   1E−300 Human calcium binding protein mRNA, complete cds 3191 M00001415A:G05 MA15:A10 BC006337 gi|3623468|gb|BC006337.1BC006337 1.5E−205 Homo sapiens, clone MGC: 12798 IMAGE: 4304127, mRNA, complete cds 3192 M00001416B:E03 MA15:B10 X57198 gi|37071|emb|X57198.1HSTFIIS Human 0 TFIIS mRNA for transcription elongation factor 3193 M00001421B:B12 MA15:H10 AF083246 gi|5106786|gb|AF083246.1HSPC028 0 Homo sapiens HSPC028 mRNA, complete cds 3194 M00005528C:E02 MA242:G04 AK054675 gi|16549267|dbj|AK054675.1AK054675 1.5E−286 Homo sapiens cDNA FLJ30113 fis, clone BNGH42000474 3195 M00023312D:F10 MA36:A10 0.47266 3196 M00022157A:C06 MA35:C04 0.05831 3197 M00022165A:A11 MA35:H04 AK000084 gi|7019941|dbj|AK000084.1AK000084 0 Homo sapiens cDNA FLJ20077 fis, clone COL02904 3198 M00022206A:B10 MA35:D10 AL137546 gi|6808228|emb|AL137546.1HSM802283   1E−293 Homo sapiens mRNA; cDNA DKFZp434A1920 (from clone DKFZp434A1920); partial cds 3199 M00003811B:F09 BC009470 gi|14495716|gb|BC009470.1BC009470 0 Homo sapiens, protein kinase, interferon- inducible double stranded RNA dependent activator, clone 3200 M00003812D:A11 AK026526 gi|10439403|dbj|AK026526.1AK026526 7.6E−137 Homo sapiens cDNA: FLJ22873 fis, clone KAT02673, highly similar to HUML12A Human ribosomal prote 3201 M00022088D:C10 MA34:G04 3202 M00003910B:C12 AF132945 gi|4680660|gb|AF132945.1AF132945 0 Homo sapiens CGI-11 protein mRNA, complete cds 3203 M00001366A:F06 MA14:A04 U24704 gi|2078477|gb|U24704.1HSU24704 0 Human antisecretory factor-1 mRNA, complete cds 3204 M00001435C:F12 MA16:B04 BC003576 gi|13097755|gb|BC003576.1BC003576   1E−300 Homo sapiens, actinin, alpha 1, clone MGC: 2358 IMAGE: 3547017, mRNA, complete cds 3205 M00001436B:E11 MA16:C04 BC003573 gi|13097746|gb|BC003573.1BC003573 0 Homo sapiens, farnesyl-diphosphate farnesyltransferase 1, clone MGC: 2200 IMAGE: 3538137, mRNA, com 3206 M00001366B:E01 MA14:D04 AK000609 gi|7020817|dbj|AK000609.1AK000609   1E−300 Homo sapiens cDNA FLJ20602 fis, clone KAT07189 3207 M00001436C:C03 MA16:D04 Z37986 gi|780262|emb|Z37986.1HSPHBIPRM   1E−300 H. sapiens mRNA for phenylalkylamine binding protein 3208 M00001437A:B01 MA16:F04 NM_000994 gi|15812220|ref|NM_000994.2 Homo 4.1E−240 sapiens ribosomal protein L32 (RPL32), mRNA 3209 M00001437B:B08 MA16:G04 AF095287 gi|3766235|gb|AF095287.1AF095287 2.5E−294 Homo sapiens pituitary tumor transforming gene protein 1 (PTTG1) mRNA, complete cds 3210 M00001467B:H05 J04456 gi|187109|gb|J04456.1HUMLEC Human 1.9E−273 14 kd lectin mRNA, complete cds 3211 M00001468A:D02 MA16:F10 U71213 gi|1621431|gb|U71213.1HSMIGST04 5.7E−127 Homo sapiens microsomal glutathione s- transferase gene, exon 4, alternatively spliced transcripts, 3212 M00007131B:B11 MA243:B04 BC017931 gi|17389843|gb|BC017931.1BC017931 0 Homo sapiens, Similar to RIKEN cDNA 1110055A02 gene, clone MGC: 23962 IMAGE: 4669658, mRNA, complet 3213 M00006650A:A10 MA241:E04 3214 M00006653C:B09 MA241:G04 0.0956 M17885 gi|190231|gb|M17885.1HUMPPARP0 2.6E−186 Human acidic ribosomal phosphoprotein P0 mRNA, complete cds 3215 M00007154B:H08 MA243:G04 BC016367 gi|16741029|gb|BC016367.1BC016367   1E−300 Homo sapiens, retinal short-chain dehydrogenase/reductase retSDR2, clone MGC: 24582 IMAGE: 4133318, 3216 M00006740A:E02 MA241:A10 3217 M00021621A:D04 MA243:A10 NM_003137 gi|15834623|ref|NM_003137.2 Homo 2.3E−285 sapiens SFRS protein kinase 1 (SRPK1), mRNA 3218 M00006740B:F11 MA241:B10 AK022929 gi|10434601|dbj|AK022929.1AK022929 4.9E−277 Homo sapiens cDNA FLJ12867 fis, clone NT2RP2003702, highly similar to Homo sapiens 17 beta-hydro 3219 M00006741C:A01 MA241:C10 AF201939 gi|9295181|gb|AF201939.1AF201939 7.6E−183 Homo sapiens DC5 (DC5) mRNA, complete cds 3220 M00022171C:A04 MA243:F10 BC000793 gb|12653990|gb|BC000793.1BC000793 0 Homo sapiens, eukaryotic translation initiation factor 1A, clone MGC: 5131 IMAGE: 3451631, mRNA, co 3221 M00026937C:B08 MA40:E05 AF151534 gi|8099341|gb|AF151534.1AF151534 9.5E−177 Homo sapiens core histone macroH2A2.2 (MACROH2A2) mRNA, complete cds 3222 M00023367A:H06 MA37:G05 0.04244 BC015958 gi|16358989|gb|BC015958.1BC015958 2.6E−257 Homo sapiens, clone MGC: 15290 IMAGE: 3940309, mRNA, complete cds 3223 M00026985C:E12 MA40:F11 BC000927 gi|12654216|gb|BC000927.1BC000927 0 Homo sapiens, Similar to poly (A) polymerase, clone MGC: 5378 IMAGE: 3445706, mRNA, complete cds 3224 M00008100A:A07 MA31:B05 AF247820 gi|13186200|gb|AF247820.3AF247820 4.1E−237 Homo sapiens NAG22 protein mRNA, complete cds 3225 M00007936B:H07 MA27:E05 BC001929 gi|12804952|gb|BC001929.1BC001929 8.4E−145 Homo sapiens, clone MGC: 3993 IMAGE: 2819500, mRNA, complete cds 3226 M00008100C:E05 MA31:F05 0.05241 AF395203 gi|15028449|gb|AF395203.1AF395203 6.5E−156 Cercopithecus aethiops DnaJ-like protein (dj2) mRNA, complete cds 3227 M00007947B:B02 MA27:E11 3228 M00004105A:C09 MA25:F05 BC010042 gi|14603152|gb|BC010042.1BC010042 1.6E−202 Homo sapiens, clone MGC: 19606 IMAGE: 3629513, mRNA, complete cds 3229 M00001433C:D09 MA23:G05 U23070 gi|1262172|gb|U23070.1HSU23070 0 Human putative transmembrane protein (nma) mRNA, complete cds 3230 M00008027B:D09 MA29:B09 M33132 gi|189423|gb|M33132.1HUMP12AA 4.8E−165 Human proliferating cell nucleolar protein P120 gene, exons 1-15 3231 M00008028D:B01 MA29:D09 AB014595 gi|3327203|dbj|AB014595.1AB014595   1E−300 Homo sapiens mRNA for KIAA0695 protein, complete cds 3232 M00008039A:C09 MA29:F09 0.04 BC013869 gi|17105403|gb|BC013869.1BC013869 2.6E−291 Homo sapiens, clone IMAGE: 3831740, mRNA 3233 M00026905A:A10 MA39:A11 AF069073 gi|3202003|gb|AF069073.1AF069073 0 Homo sapiens P8 protein mRNA, complete cds 3234 M00026905D:C05 MA39:C11 BC010631 gi|14714946|gb|BC010631.1BC010631 3.3E−281 Homo sapiens, clone IMAGE: 3867552, mRNA 3235 M00001401B:A06 MA15:G05 U90313 gi|2393721|gb|U90313.1HSU90313 0 Human glutathione-S-transferase homolog mRNA, complete cds 3236 M00001402A:A08 MA15:H05 0.03584 X74215 gi|414045|emb|X74215.1HSLON   7E−181 H. sapiens mRNA for Lon protease-like protein 3237 M00005534C:E12 MA242:A05 0.55385 3238 M00005542A:D09 MA242:D05 NM_001428 gi|16507965|ref|NM_001428.2 Homo 1.1E−218 sapiens enolase 1, (alpha) (ENO1), mRNA 3239 M00007031D:E02 MA240:F11 NM_005463 gi|14110410|ref|NM_005463.2 Homo 2.8E−186 sapiens heterogeneous nuclear ribonucleoprotein D-like (HNRPDL), transcript variant 1, mRNA 3240 M00007032A:D04 MA240:G11 D89678 gi|3218539|dbj|D89678.1D89678 Homo 5.2E−225 sapiens mRNA for A+U-rich element RNA binding factor, complete cds 3241 M00005813C:F12 MA242:H11 BC000659 gi|12653746|gb|BC000659.1BC000659 1.8E−245 Homo sapiens, clone MGC: 1004 IMAGE: 3347423, mRNA, complete cds 3242 SL163 MA248:B05 0.82548 3243 SL164 MA248:C05 0.43491 AF415175 gi|16589063|gb|AF415175.1AF415175 4.9E−102 Homo sapiens putative SH3 domain- containing guanine exchange factor SGEF (SGEF) mRNA, complete cd 3244 SL167 MA248:F05 0.13452 AK025140 gi|10437598|dbj|AK025140.1AK025140 5.5E−159 Homo sapiens cDNA: FLJ21487 fis, clone COL05419 3245 SL168 MA248:G05 0.72115 3246 SL169 MA248:H05 3247 M00023320B:A03 MA36:H11 BC006428 gi|13623618|gb|BC006428.1BC006428 6.8E−298 Homo sapiens, hypothetical protein, clone MGC: 12969 IMAGE: 3343683, mRNA, complete cds 3248 M00005350B:F10 MA246:C05 BC014191 gi|15559670|gb|BC014191.1BC014191 4.7E−218 Homo sapiens, clone MGC: 20633 IMAGE: 4761663, mRNA, complete cds 3249 M00008069D:F01 MA30:B05 0.09317 3250 M00022165B:C08 MA35:B05 BC012585 gi|15214891|gb|BC012585.1BC012585 5.4E−199 Homo sapiens, clone IMAGE: 4332982, mRNA 3251 M00022165C:E12 MA35:D05 NM_001024 gi|14670385|ref|NM_001024.2 Homo   4E−184 sapiens ribosomal protein S21 (RPS21), mRNA 3252 M00022166C:E07 MA35:E05 D87717 gi|1663709|dbj|D87717.1D87717 Human 1.8E−139 mRNA for KIAA0013 gene, complete cds 3253 M00008072D:E12 MA30:F05 BC007581 gi|14043186|gb|BC007581.1BC007581 6.5E−264 Homo sapiens, aldehyde dehydrogenase 4 family, member A1, clone MGC: 15564 IMAGE: 3139944, mRNA, co 3254 M00022211B:D05 MA35:A11 AK025494 gi|10438028|dbj|AK025494.1AK025494 2.3E−226 Homo sapiens cDNA: FLJ21841 fis, clone HEP01831 3255 M00008089A:E09 MA30:G11 AB050577 gi|14317901|dbj|AB050577.1AB050577 1.1E−231 Homo sapiens NUF2 mRNA for kinetochore protein Nuf2, complete cds 3256 M00003974D:E04 MA24:C11 AF136185 gi|6625654|gb|AF136185.1AF136185 3.5E−228 Homo sapiens collagen type XVII (COL17A1) gene, 3' UTR, long form 3257 M00003980D:F10 MA24:F11 AF150100 gi|5107187|gb|AF150100.1AF150100   5E−252 Homo sapiens small zinc finger-like protein (TIM9a) mRNA, complete cds 3258 M00003984D:C08 MA24:H11 AL133560 gi|6599130|emb|AL133560.1HSM801406 0 Homo sapiens mRNA; cDNA DKFZp434M1414 (from clone DKFZp434M1414); partial cds 3259 M00023373D:A01 MA22:E05 AK023875 gi|10435944|dbj|AK023875.1AK023875 2.2E−201 Homo sapiens cDNA FLJ13813 fis, clone THYRO1000358, moderately similar to SELENIUM-BINDING LIVER 3260 M00023396D:D01 MA22:H05 0.48026 3261 M00001437D:E12 MA16:A05 M30684 gi|177064|gb|M30684.1GORMHCBAA 2.3E−260 Gorilla gorilla beta-2-microglobulin mRNA (GOGOB2M) 3262 M00001438A:B09 MA16:B05 BC005230 gi|13528857|gb|BC005230.1BC005230 3.6E−259 Homo sapiens, ubiquinol-cytochrome c reductase binding protein, clone MGC: 12253 IMAGE: 3961169, mR 3263 M00001369A:C07 MA14:E05 AF097514 gi|4808600|gb|AF097514.1AF097514 2.2E−229 Homo sapiens stearoyl-CoA desaturase (SCD) mRNA, complete cds 3264 M00001439C:A07 MA16:F05 BC017270 gi|16878126|gb|BC017270.1BC017270 3.7E−106 Homo sapiens, homolog of yeast long chain polyunsaturated fatty acid elongation enzyme 2, clone M 3265 M00001369C:A05 MA14:H05 AF190167 gi|6456117|gb|AF190167.1AF190167   1E−300 Homo sapiens membrane associated protein SLP-2 (HUSLP2) mRNA, complete cds 3266 M00001468D:B11 MA16:A11 BC008442 gi|14250074|gb|BC008442.1BC008442 5.3E−149 Homo sapiens, Similar to transmembrane 4 superfamily member 1, clone MGC: 14656 IMAGE: 4101110, mRN 3267 M00001386B:F08 MA14:B11 AF132818 gi|6580834|gb|AF132818.1AF132818   3E−169 Homo sapiens colon Kruppel-like factor (CKLF) mRNA, complete cds 3268 M00001387A:A08 MA14:F11 NM_022551 gi|14165467|ref|NM_022551.2 Homo   7E−298 sapiens ribosomal protein S18 (RPS18), mRNA 3269 M00007163A:B10 MA243:B05 D29013 gi|517113|dbj|D29013.1HUMLNCAP 1.5E−178 Human mRNA for DNA polymerase beta, complete cds 3270 M00006675C:A06 MA241:E05 BC009534 gi|16306927|gb|BC009534.1BC009534 3.1E−250 Homo sapiens, clone IMAGE: 3891886, mRNA, partial cds 3271 M00007191C:A06 MA243:G05 BC001765 gi|12804678|gb|BC001765.1BC001765 1.7E−295 Homo sapiens, Similar to stromal antigen 2, clone MGC: 1282 IMAGE: 3352347, mRNA, complete cds 3272 M00006678A:D02 MA241:H05 NM_002475 gi|17986280|ref|NM_002475.2 Homo   1E−240 sapiens myosin light chain 1 slow a (MLC1SA), mRNA 3273 M00026941C:A12 MA40:E06 BC018910 gi|17511916|gb|BC018910.1BC018910 2.6E−149 Homo sapiens, clone MGC: 10643 IMAGE: 3959973, mRNA, complete cds 3274 M00026996A:E01 MA40:E12 0.05985 AF238079 gi|7542489|gb|AF238079.1AF238079 0 Homo sapiens FK506 binding protein precursor (FKBP19) mRNA, complete cds 3275 M00023401B:E06 MA37:G12 0.71373 3276 M00027005B:D03 MA40:H12 AL137626 gi|6808422|emb|AL137626.1HSM802390 5.8E−289 Homo sapiens mRNA; cDNA DKFZp434O0712 (from clone DKFZp434O0712); partial cds 3277 M00007937B:A02 MA27:C06 Z18948 gi|396712|emb|Z18948.1HSS100E 1.3E−174 H. sapiens mRNA for S100E calcium binding protein 3278 M00021612C:E11 MA31:C06 0.60788 AB032969 gi|6329965|dbj|AB032969.1AB032969 1.2E−92 Homo sapiens mRNA for KIAA1143 protein, partial cds 3279 M00007938C:C12 MA27:G06 BC002360 gi|12803112|gb|BC002360.1BC002360 3.1E−122 Homo sapiens, U5 snRNP-specific protein, 116 kD, clone MGC: 8581 IMAGE: 2960986, mRNA, complete cds 3280 M00001623C:A06 MA23:F12 BC000629 gi|12653688|gb|BC000629.1BC000629 9.9E−238 Homo sapiens, Similar to aspartyl-tRNA synthetase, clone MGC: 1562 IMAGE: 3344322, mRNA, complete c 3281 M00001630D:A11 MA23:G12 AF179626 gi|6457296|gb|AF179626.1AF179626 1.7E−298 Expression vector pGP100, complete sequence 3282 M00008044B:E11 MA29:A11 AF083420 gi|5326765|gb|AF083420.1AF083420 4.5E−268 Homo sapiens brain-specific STE20-like protein kinase 3 (STK3) mRNA, complete cds 3283 M00008044C:C10 MA29:B11 AF224759 gi|12043739|gb|AF224759.1AF224759 1.3E−277 Homo sapiens adenocarcinoma antigen ART1/P17 mRNA, complete cds 3284 M00008044D:B08 MA29:C11 0.82704 BC019356 gi|17939588|gb|BC019356.1BC019356 5.4E−27 Homo sapiens, clone IMAGE: 3503646, mRNA 3285 M00008044D:C05 MA29:D11 M23161 gi|339899|gb|M23161.1HUMTRANSC 5.4E−160 Human transposon-like element mRNA 3286 M00022074C:A04 MA33:E11 3287 M00026910C:D12 MA39:E12 J03037 gi|179771|gb|J03037.1HUMCAIIA Human 2.4E−263 carbonic anhydrase II mRNA, complete cds 3288 M00026913A:D06 MA39:G12 AK058163 gi|16554226|dbj|AK058163.1AK058163 2.9E−275 Homo sapiens cDNA FLJ25434 fis, clone TST06728, highly similar to ELONGATION FACTOR 1-ALPHA 1 3289 M00001402C:H08 MA15:D06 BC000461 gi|12653382|gb|BC000461.1BC000461 0 Homo sapiens, eukaryotic translation initiation factor 2, subunit 2 (beta, 38 kD), clone MGC: 8508 3290 M00001404C:C11 MA15:F06 BC001497 gi|16306642|gb|BC001497.1BC001497 1.4E−286 Homo sapiens, clone MGC: 2068 IMAGE: 2823581, mRNA, complete cds 3291 M00005587B:G05 MA242:C06 BC001566 gi|16306756|gb|BC001566.1BC001566 8.5E−282 Homo sapiens, clone IMAGE: 3451980, mRNA, partial cds 3292 M00006934D:D10 MA240:C06 D63861 gi|1769811|dbj|D63861.1D63861 Homo 7.5E−142 sapiens DNA for cyclophilin 40, complete cds 3293 SL176 MA248:G06 3294 M00023295D:E05 MA36:A06 M16957 gi|188249|gb|M16957.1HUMMHDRA2D 5.2E−227 Human MHC class II HLA-DR2 (Dw2) b- associated glycoprotein beta-chain mRNA, 3′ end 3295 M00023320B:C02 MA36:A12 3296 M00005401B:F12 MA246:B12 U47742 gi|1517913|gb|U47742.1HSU47742 4.4E−54 Human monocytic leukaemia zinc finger protein (MOZ) mRNA, complete cds 3297 M00008074D:C05 MA30:F06 AF035289 gi|2661043|gb|AF035289.1AF035289 3.3E−197 Homo sapiens clone 23969 mRNA sequence 3298 M00022175B:F06 MA35:G06 U81002 gi|4580010|gb|U81002.1HSU81002 Homo 1.1E−212 sapiens TRAF4 associated factor 1 mRNA, partial cds 3299 M00022230B:C10 MA35:G12 BC019061 gi|17512149|gb|BC019061.1BC019061 7.5E−149 Homo sapiens, Similar to RIKEN cDNA 1500019E20 gene, clone IMAGE: 5089739, mRNA 3300 M00022093C:C08 MA34:C06 AB061831 gi|17932955|dbj|AB061831.1AB061831 1.1E−184 Homo sapiens RPL32 gene for ribosomal protein L32, complete cds and sequence 3301 M00022093C:C12 MA34:D06 BC009401 gi|14424786|gb|BC009401.1BC009401 9.9E−294 Homo sapiens, natural killer cell transcript 4, clone MGC: 15353 IMAGE: 4300407, mRNA, complete cds 3302 M00022132A:H07 MA34:F12 BC015557 gi|15990394|gb|BC015557.1BC015557   1E−300 Homo sapiens, clone MGC: 1567 IMAGE: 3050731, mRNA, complete cds 3303 M00023397B:D04 MA22:A06 AF083441 gi|5813822|gb|AF083441.1AF083441   1E−300 Homo sapiens SUI1 isolog mRNA, complete cds 3304 M00023399D:G04 MA22:E06 BC004450 gi|13325265|gb|BC004450.1BC004450   1E−300 Homo sapiens, hypothetical protein MGC2650, clone MGC: 4188 IMAGE: 2820830, mRNA, complete cds 3305 M00001439D:C09 MA16:A06 BC002446 gi|12803262|gb|BC002446.1BC002446 0 Homo sapiens, MRJ gene for a member of the DNAJ protein family, clone MGC: 1152 IMAGE: 3346070, mRN 3306 M00001441A:A09 MA16:B06 M57710 gi|179530|gb|M57710.1HUMBPIGE 1.7E−295 Human IgE-binding protein (epsilon-BP) mRNA, complete cds 3307 M00001369D:E02 MA14:C06 AF034546 gi|3127052|gb|AF034546.1AF034546 1.9E−195 Homo sapiens sorting nexin 3 (SNX3) mRNA, complete cds 3308 M00001371D:H10 MA14:E06 3309 M00001372A:D01 MA14:F06 AF151872 gi|4929696|gb|AF151872.1AF151872 0 Homo sapiens CGI-114 protein mRNA, complete cds 3310 M00001444C:F03 MA16:G06 AL359678 gi|15215911|emb|AL359678.15AL359678 0 Human DNA sequence from clone RP11- 550J21 on chromosome 9, complete sequence [Homo sapiens] 3311 M00001445A:B02 BC003401 gi|13097293|gb|BC003401.1BC003401 9.7E−291 Homo sapiens, ribosomal protein S14, clone MGC: 5429 IMAGE: 3448752, mRNA, complete cds 3312 M00001388D:F11 MA14:D12 BC002609 gi|12803554|gb|BC002609.1BC002609 0 Homo sapiens, chromobox homolog 1 (Drosophila HP1 beta), clone MGC: 1267 IMAGE: 3140815, mRNA, comp 3313 M00001481C:A12 MA16:F12 AB033007 gi|6330242|dbj|AB033007.1AB033007 2.9E−88 Homo sapiens mRNA for KIAA1181 protein, partial cds 3314 M00001389B:B05 MA14:G12 BC013858 gi|15426627|gb|BC013858.1BC013858   2E−239 Homo sapiens, clone IMAGE: 3869909, mRNA 3315 M00001389C:G01 MA14:H12 0.07529 AY004872 gi|9508996|gb|AY004872.1 Homo sapiens 4.6E−175 thioredoxin (TXN) mRNA, complete cds 3316 M00001482D:D11 MA16:H12 0.07738 BC009982 gi|14602997|gb|BC009982.1BC009982 5.1E−169 Homo sapiens, clone IMAGE: 4121355, mRNA, partial cds 3317 M00006809B:F04 MA241:D12 0.62333 3318 I:3325119:07A01:A01 MA127:A01 U21936 gi|717118|gb|U21936.1HSU21936 Human 1.4E−149 peptide transporter (HPEPT1) mRNA, complete cds 3319 I:3033345:07A01:C01 MA127:C01 BC004982 gi|13436412|gb|BC004982.1BC004982   9E−229 Homo sapiens, glucose phosphate isomerase, clone MGC: 3935 IMAGE: 2906270, mRNA, complete cds 3320 I:3176222:07A01:E07 MA127:E07 U09413 gi|488554|gb|U09413.1HSU09413 Human 1.9E−264 zinc finger protein ZNF135 mRNA, complete cds 3321 I:2510627:07B01:G07 MA129:G07 BC002803 gi|12803912|gb|BC002803.1BC002803   1E−300 Homo sapiens, hypothetical protein, clone MGC: 3402 IMAGE: 3636703, mRNA, complete cds 3322 I:1705208:06B01:A01 MA125:A01 X52541 gi|31129|emp|X52541.1HSEGR1 Human 0 mRNA for early growth response protein 1 (hEGR1) 3323 I:1672781:06B01:C07 MA125:C07 BC010042 gi|14603152|gb|BC010042.1BC010042   1E−300 Homo sapiens, clone MGC: 19606 IMAGE: 3629513, mRNA, complete cds 3324 I:1712888:06B01:D07 MA125:D07 AL137469 gi|6808076|emb|AL137469.1HSM802187   1E−300 Homo sapiens mRNA; cDNA DKFZp434P2422 (from clone DKFZp434P2422); partial cds 3325 I:1696224:06B01:E07 MA125:E07 NM_005346 gi|5579470|ref|NM_005346.2 Homo   1E−300 sapiens heat shock 70 kD protein 1B (HSPA1B), mRNA 3326 I:3935034:06B01:H07 MA125:H07 BC007616 gi|14043251|gb|BC007616.1BC007616 1.2E−249 Homo sapiens, clone MGC: 15728 IMAGE: 3354330, mRNA, complete cds 3327 I:1800114:03A01:E01 MA111:E01 M24559 gi|514365|gb|M24559.1HUMIGRPOLY 1.5E−205 Human poly-Ig receptor transmembrane secretory component mRNA, 3′ end 3328 I:1976029:03A01:D07 MA111:D07 BC000629 gi|12653688|gb|BC000629.1BC000629 1.1E−299 Homo sapiens, Similar to aspartyl-tRNA synthetase, clone MGC: 1562 IMAGE: 3344322, mRNA, complete c 3329 I:1439934:03B01:E07 MA113:E07 0.17464 M64788 gi|190855|gb|M64788.1HUMRAP1GAP 5.9E−184 Human GTPase activating protein (rap1GAP) mRNA, complete cds 3330 I:2512879:01A01:C01 MA103:C01 M12271 gi|178091|gb|M12271.1HUMADH1CB 3.7E−290 Homo sapiens class I alcohol dehydrogenase (ADH1) alpha subunit mRNA, complete cds 3331 I:2900277:01B01:B07 MA105:B07 BC015492 gi|15930098|gb|BC015492.1BC015492   1E−300 Homo sapiens, clone MGC: 8967 IMAGE: 3915505, mRNA, complete cds 3332 I:1479255:01A01:C07 MA103:C07 NM_002245 gi|15451900|ref|NM_002245.2 Homo   1E−300 sapiens potassium channel, subfamily K, member 1 (TWIK-1) (KCNK1), mRNA 3333 I:2648612:04B01:A01 MA117:A01 NM_006013 gi|15718685|ref|NM_006013.2 Homo   1E−300 sapiens ribosomal protein L10 (RPL10), mRNA 3334 I:1889867:04A01:C01 MA115:C01 AF004563 gi|3041874|gb|AF004563.1AF004563 8.2E−148 Homo sapiens hUNC18b alternatively- spliced mRNA, complete cds 3335 I:1858905:04A01:D01 MA115:D01 BC015520 gi|15930171|gb|BC015520.1BC015520 1.8E−211 Homo sapiens, ribonuclease, RNase A family, 4, clone MGC: 9306 IMAGE: 3905439, mRNA, complete cds 3336 I:2591494:04B01:H01 MA117:H01 BC009084 gi|14290606|gb|BC009084.1BC009084 0 Homo sapiens, Similar to selenium binding protein 1, clone MGC: 9270 IMAGE: 3853674, mRNA, complete 3337 I:2916261:04B01:A07 MA117:A07 BC016855 gi|16877177|gb|BC016855.1BC016855 5.9E−289 Homo sapiens, clone MGC: 17066 IMAGE: 3850361, mRNA, complete cds 3338 I:2397815:04B01:B07 MA117:B07 BC007888 gi|14043894|gb|BC007888.1BC007888 3.3E−253 Homo sapiens, eukaryotic translation initiation factor 2, subunit 2 (beta, 38 kD), clone MGC: 1417 3339 I:2182095:04B01:D07 MA117:D07 NM_002580 gi|4505604|ref|NM_002580.1 Homo 5.8E−289 sapiens pancreatitis-associated protein (PAP), mRNA 3340 I:2506194:02A01:A01 MA107:A01 U36601 gi|1036798|gb|U36601.1HSU36601 Homo 1.3E−240 sapiens heparan N-deacetylase/N- sulfotransferase-2 mRNA, complete cds 3341 I:1806219:02A01:C01 MA107:C01 U34279 gi|1236798|gb|U34279.1HSU34279 5.4E−202 Human uroguanylin mRNA, complete cds 3342 I:1729724:02A01:G07 MA107:G07 NM_002487 gi|10800414|ref|NM_002487.2 Homo 3.1E−169 sapiens necdin homolog (mouse) (NDN), mRNA 3343 I:1886842:05A02:G01 MA120:G01 BC010578 gi|14714852|gb|BC010578.1BC010578 1.5E−292 Homo sapiens, clone MGC: 9344 IMAGE: 3458845, mRNA, complete cds 3344 I:1352669:05A02:B07 MA120:B07 0.10093 BC016752 gi|16876952|gb|BC016752.1BC016752 1.4E−169 Homo sapiens, clone IMAGE: 2959721, mRNA 3345 I:1755847:05B02:C07 MA122:C07 U51095 gi|1777771|gb|U51095.1HSUS1095 5.9E−230 Human homeobox protein Cdx1 mRNA, complete cds 3346 I:1803418:05B02:D07 MA122:D07 BC006168 gi|13544071|gb|1BC006168.1BC006168 0 Homo sapiens, clone IMAGE: 3960207, mRNA, partial cds 3347 I:1568725:05B02:F07 MA122:F07 0.36394 D49410 gi|684968|dbj|D49410.1HUMIL3RA12 7.7E−187 Homo sapiens gene for interleukin 3 receptor alpha subunit, exon 12 and partial cds 3348 I:1857708:05A02:G07 MA120:G07 U43381 gi|1155348|gb|U43381.1HSU43381 1.3E−283 Human Down Syndrome region of chromosome 21 DNA 3349 I:1687060:05B02:G07 MA122:G07 U57645 gi|1816511|gb|U57645.1HSU57645 3.3E−281 Human helix-loop-helix proteins Id-1 (ID- 1) and Id-1′ (ID-1) genes, complete cds 3350 I:3407289:07A02:A07 MA128:A07 0.21116 AB011135 gi|3043649|dbj|AB011135.1AB011135 1.7E−68 Homo sapiens mRNA for KIAA0563 protein, complete cds 3351 I:1235535:07A02:B07 MA128:B07 NM_001012 gi|4506742|ref|NM_001012.1 Homo 3.8E−156 sapiens ribosomal protein S8 (RPS8), mRNA 3352 I:1525795:03B02:D07 MA114:D07 X05360 gi|29838|emb|X05360.1HSCDC2 Human 1.5E−289 CDC2 gene involved in cell cycle control 3353 I:3744592:03A02:H07 MA112:H07 S76992 gi|913345|gb|S76992.1S76992   1E−194 VAV2 = VAV oncogene homolog [human, fetal brain, mRNA Partial, 2753 nt] 3354 I:1485817:01A02:B01 MA104:B01 L14787 gi|292930|gb|L14787.1HUMZFPA Human 3.4E−247 DNA-binding protein mRNA, 3′end 3355 I:2365149:01B02:B01 MA106:B01 U58917 gi|2826475|gb|U58917.1HSU58917 Homo   9E−208 sapiens IL-17 receptor mRNA, complete cds 3356 I:1439677:01A02:D01 MA104:D01 AL096780 gi|5420184|emb|AL096780.1HS384D86A 1.8E−146 Novel human gene mapping to chomosome 22p13.33 similar to mouse Choline/Ethanolamine Kinase (O55 3357 I:2372275:01B02:G01 MA106:G01 BC019252 gi|17939418|gb|BC019252.BC019252   1E−300 Homo sapiens, clone MGC: 1111 IMAGE: 3503549, mRNA, complete cds 3358 I:3211615:01B02:H01 MA106:H01 BC013808 gi|15489437|gb|BC013808.1BC013808   2E−230 Homo sapiens, TATA box binding protein (TBP)-associated factor, RNA polymerase I, A, 48 kD, clone 3359 I:2368282:01B02:B07 MA106:B07 AK056794 gi|16552300|dbj|AK056794.1AK056794 5.8E−209 Homo sapiens cDNA FLJ32232 fis, clone PLACE6004578, highly similar to CYTOCHROME P450 11A1, MITO 3360 I:1737833:04A02:D01 MA116:D01 D26598 gi|565646|dbj|D26598.1HUMPSH1   1E−300 Human mRNA for proteasome subunit HsC10-II, complete cds 3361 I:2382192:04B02:F01 MA118:F01 Y12653 gi|2546963|emb|Y12653.1HSDIUBIQU 1.6E−264 H. sapiens mRNA for diubiquitin 3362 I:1958902:04A02:D07 MA116:D07 D87258 gi|1513058|dbj|D87258.1D87258 Homo 0 sapiens mRNA for serin protease with IGF-binding motif, complete cds 3363 I:1704472:04B02:G07 MA118:G07 U66871 gi|1519518|gb|U66871.1HSU66871   7E−161 Human enhancer of rudimentary homolog mRNA, complete cds 3364 I:1903767:04A02:H07 MA116:H07 AF025304 gi|2739055|gb|AF025304.1AF025304   1E−300 Homo sapiens protein-tyrosine kinase EPHB2v (EPHB2) mRNA, complete cds 3365 I:1268080:02A02:C01 MA108:C01 AB006631 gi|14133200|dbj|AB006631.2AB006631 0 Homo sapiens mRNA for KIAA0293 gene, partial cds 3366 I:1347384:02A02:C07 MA108:C07 U78579 gi|1743878|gb|U78579.1HSU78579 0 Human type I phosphatidylinositol-4- phosphate 5-kinase beta (STM7) mRNA, partial cds 3367 I:2344817:08B01:H02 MA133:H02 3368 I:3236109:08A01:B08 MA131:B08 0.46441 3369 I:2832506:07A01:H08 MA127:H08 BC000851 gi|12654082|gb|BC000851.1BC000851 8.5E−282 Homo sapiens, ribosomal protein L13, clone IMAGE: 3458439, mRNA 3370 I:1673876:06B01:B02 MA125:B02 V00568 gi|34815|emb|V00568.1HSMYC1 Human   1E−300 mRNA encoding the c-myc oncogene 3371 I:3686211:06B01:E02 MA125:E02 X59960 gi|402620|emb|X59960.1HSSPMYEL   1E−300 H. sapiens mRNA for sphingomyelinase 3372 I:2449837:06B01:H02 MA125:H02 BC000070 gi|2652644|gb|BC000070.1BC000070   3E−219 Homo sapiens, small nuclear ribonucleoprotein polypeptide G, clone MGC: 1614 IMAGE: 3503973, mRNA, 3373 I:1613874:06B01:C08 MA125:C08 AF019952 gi|2655036|gb|AF019952.1AF019952 0 Homo sapiens tumor suppressing STF cDNA 1 (TSSC1) mRNA, complete cds 3374 I:1813409:03A01:C02 MA111:C02 BC009244 gi|14328061|gb|BC009244.1BC009244   1E−300 Homo sapiens, isocitrate dehydrogenase 2 (NADP+), mitochondrial, clone MGC: 3700 IMAGE: 2959540, mR 3375 I:1975514:03A01:A08 MA111:A08 S52873 gi|263656|gb|S52873.1S52873 cytidine 5.7E−286 deaminase [human, monocytoid cell line U937, mRNA Partial, 736 nt] 3376 I:1403294:01A01:B02 MA103:B02 0.13199 3377 I:2414624:01B01:D02 MA105:D02 U31278 gi|950198|gb|U31278.1HSU31278 Homo 0 sapiens mitotic feedback control protein Madp2 homolog mRNA, complete cds 3378 I:2901811:01B01:H02 MA105:H02 BC013081 gi|15341817|gb|BC013081.1BC013081 2.6E−213 Homo sapiens, Similar to metallothionein 3 (growth inhibitory factor (neurotrophic)), clone MGC: 1 3379 I:2683564:01B01:B08 MA105:B08 V00522 gi|32122|emb|V00522.1HSHL01 Human 2.5E−294 mRNA encoding major histocompatibility complex gene HLA-DR beta-I 3380 I:2725511:01B01:C08 MA105:C08 AF004849 gi|2627330|gb|AF004849.1AF004849 1.4E−177 Homo sapiens PKY protein kinase mRNA, complete cds 3381 I:1431273:04A01:A02 MA115:A02 M82962 gi|535474|gb|M82962.1HUMPPH Human   1E−268 N-benzoyl-L-tyrosyl-p-amino-benzoic acid hydrolase alpha subunit (PPH alpha) mRNA, complete cds 3382 I:1636639:04B01:A02 MA117:A02 AF055009 gi|3005731|gb|AF055009.1AF055009 0 Homo sapiens clone 24747 mRNA sequence 3383 I:2455617:04B01:D02 MA117:D02 BC008281 gi|14249818|gb|BC008281.1BC008281 3.2E−281 Homo sapiens, guanosine monophosphate reductase, clone MGC: 10464 IMAGE: 3635871, mRNA, complete cd 3384 I:2952504:04B01:F02 MA117:F02 U72849 gi|4097996|gb|U72849.1HSAPEVPL7   1E−300 Homo sapiens envoplakin (EVPL) gene, exon 22 and complete cds 3385 I:1483847:04A01:A08 MA115:A08 AF026293 gi|2559011|gb|AF026293.1AF026293   4E−93 Homo sapiens chaperonin containing t- complex polypeptide 1, beta subunit (Cctb) mRNA, complete cds 3386 I:2923150:04B01:B08 MA117:B08 M18963 gi|190978|gb|M18963.1HUMREGA 1.2E−237 Human islet of Langerhans regenerating protein (reg) mRNA, complete cds 3387 I:1813133:04A01:F08 MA115:F08 X12597 gi|32326|emb|X12597.1HSHMG1 Human 1.3E−255 mRNA for high mobility group-1 protein (HMG-1) 3388 I:2510171:04B01:H08 MA117:H08 0.15344 X04503 gi|36490|emb|X04503.1HSSLIPR Human 1.1E−259 SLPI mRNA fragment for secretory leucocyte protease inhibitor 3389 I:2190284:02A01:H02 MA107:H02 D84107 gi|1669546|dbj|D84107.1D84107 Homo 0 sapiens mRNA for RBP-MS/type 1, complete cds 3390 I:1522716:05B02:B02 MA122:B02 X56134 gi|37849|emb|X56134.1HSVIMENT 0 Human mRNA for vimentin 3391 I:1901271:05A02:G02 MA120:G02 U90916 gi|1913897|gb|U90916.1HSU90916   9E−288 Human clone 23815 mRNA sequence 3392 I:1820522:05B02:H02 MA122:H02 BC002806 gi|12803918|gb|BC002806.1BC002806 1.1E−299 Homo sapiens, phosphatidic acid phosphatase type 2C, clone MGC: 3813 IMAGE: 3659728, mRNA, complete 3393 I:2365295:05A02:A08 MA120:A08 BC015460 gi|15930032|gb|BC015460.1BC015460 3.8E−26 Homo sapiens, Similar to glutaminyl- peptide cyclotransferase (glutaminyl cyclase), clone IMAGE: 39 3394 I:1335140:05A02:C08 MA120:C08 X02152 gi|34312|emb|X02152.1HSLDHAR 0 Human mRNA for lactate dehydrogenase- A (LDH-A, EC 1.1.1.27) 3395 I:1822577:05B02:D08 MA122:D08 BC001941 gi|12804976|gb|BC001941.1BC001941 1.7E−270 Homo sapiens, tissue specific transplantation antigen P35B, clone MGC: 4302 IMAGE: 2819332, mRNA, c 3396 I:1306814:06B02:A08 MA126:A08 AK026649 gi|10439547|dbj|AK026649.1AK026649 9.8E−135 Homo sapiens cDNA: FLJ22996 fis, clone KAT11938 3397 I:3034694:06B02:D08 MA126:D08 BC008935 gi|14286273|gb|BC008935.1BC008935 4.6E−299 Homo sapiens, Similar to solute carrier family 25 (mitochondrial carrier; adenine nucleotide tran 3398 I:1453049:03B02:A02 MA114:A02 X76180 gi|452649|emb|X76180.1HSLASNA 2.7E−269 H. sapiens mRNA for lung amiloride sensitive Na+ channel protein 3399 I:1453748:03B02:D02 MA114:D02 BC013579 gi|15488897|gb|BC013579.1BC013579 2.6E−135 Homo sapiens, Similar to calpastatin, clone MGC: 9402 IMAGE: 3878564, mRNA, complete cds 3400 I:3001492:03A02:G02 MA112:G02 X75042 gi|402648|emb|X75042.1HSRNAREL 1.6E−295 H. sapiens rel proto-oncogene mRNA 3401 I:3876715:03A02:C08 MA112:C08 BC000373 gi|12653210|gb|BC000373.1BC000373 6.4E−161 Homo sapiens, Similar to amyloid beta (A4) precursor-like protein 2, clone MGC: 8371 IMAGE: 2820109 3402 I:2992851:03A02:D08 MA112:D08 AF190637 gi|10441643|gb|AF190637.1AF190637 1.5E−286 Homo sapiens nephrin mRNA, complete cds 3403 I:1500649:03B02:G08 MA114:G08 AB008430 gi|2766164|dbj|AB008430.1AB008430   1E−234 Homo sapiens mRNA for CDEP, complete cds 3404 I:1512943:01A02:B02 MA104:B02 AJ005036 gi|3059108|emb|AJ005036.1HSAJ5036 9.1E−288 Homo sapiens mRNA for phosphodiesterase 3A (from corpus cavernosum) 3405 I:1467565:01A02:D02 MA104:D02 BC014991 gi|15929072|gb|BC014991.1BC014991 3.7E−262 Homo sapiens, clone MGC: 23226 IMAGE: 4909112, mRNA, complete cds 3406 I:2455118:01B02:D08 MA106:D08 X16396 gi|35070|emb|X16396.1HSNMTDC 0 Human mRNA for NAD-dependent methylene tetrahydrofolate dehydrogenase cyclohydrolase (EC 1.5.1.15) 3407 I:2840251:01B02:E08 MA106:E08 U52513 gi|1777781|gb|U52513.1HSU52513 0 Human RIG-G mRNA, complete cds 3408 I:2911347:10B02:E02 MA67:E02 0.28302 3409 I:1812030:10B02:G08 MA67:G08 AB049758 gi|10800085|dbj|AB049758.1AB049758 3.6E−200 Homo sapiens mawbp mRNA for MAWD binding protein, complete cds 3410 I:2663606:04B02:F08 MA118:F08 U37690 gi|1017824|gb|U37690.1HSU37690 5.2E−196 Human RNA polymerase II subunit (hsRPB10) mRNA, complete cds 3411 I:1308333:02A02:E02 MA108:E02 BC017338 gi|16878283|gb|BC017338.1BC017338 1.4E−286 Homo sapiens, fucosidase, alpha-L-1, tissue, clone MGC: 29579 IMAGE: 4871788, mRNA, complete cds 3412 I:1578941:02B02:E02 MA110:E02 AK058013 gi|16554011|dbj|AK058013.1AK058013 1.2E−246 Homo sapiens cDNA FLJ25284 fis, clone STM06787, highly similar to 15- HYDROXYPROSTAGLANDIN DEHYDR 3413 I:1535439:02A02:D08 MA108:D08 M83363 gi|190096|gb|M83363.1HUMPMCA 3.1E−250 Human plasma membrane calcium- pumping ATPase (PMCA4) mRNA, complete cds 3414 I:1857475:02B02:H08 MA110:H08 AF009203 gi|2454508|gb|AF009203.1AF009203 1.5E−292 Homo sapiens YAC clone 377A1 unknown mRNA, 3′untranslated region 3415 I:2908878:08B01:F09 MA133:F09 0.46085 3416 I:2830575:07A01:C03 MA127:C03 0.06365 D16431 gi|598955|dbj|D16431.1HUMHDGF 1.7E−289 Human mRNA for hepatoma-derived growth factor, complete cds 3417 I:1557906:07B01:G03 MA129:G03 AK057477 gi|16553199|dbj|AK057477.1AK057477 5.8E−230 Homo sapiens cDNA FLJ32915 fis, clone TESTI2006425 3418 I:2200604:06B01:F03 MA125:F03 U47105 gi|4457236|gb|U47105.2HSU47105 Homo 0 sapiens H105e3 (H105e3) mRNA, complete cds 3419 I:1653326:06A01:C09 MA123:C09 BC01888 gi|17403014|gb|BC018881.1BC018881   1E−296 Homo sapiens, clone IMAGE: 3617364, mRNA 3420 I:1720149:06A01:G09 MA123:G09 U48959 gi|7239695|gb|U48959.2HSU48959 Homo 2.4E−291 sapiens myosin light chain kinase (MLCK) mRNA, complete cds 3421 I:1560987:03B01:G03 MA113:G03 U17077 gi|1000711|gb|U17077.1HSU17077 2.3E−92 Human BENE mRNA, partial cds 3422 I:1510714:03B01:G09 MA113:G09 NM_000240 gi|4557734|ref|NM_000240.1 Homo 6.3E−264 sapiens monoamine oxidase A (MAOA), nuclear gene encoding mitochondrial protein, mRNA 3423 I:2501484:01B01:A03 MA105:A03 AB002438 gi|2943813|dbj|AB002438.1AB002438 1.1E−268 Homo sapiens mRNA from chromosome 5q21-22, clone: FBR89 3424 I:1379063:01A01:B03 MA103:B03 U28055 gi|1141776|gb|U28055.1HSU28055 Homo 0 sapiens hepatocyte growth factor-like protein homolog mRNA, partial cds 3425 I:2797902:01B01:C03 MA105:C03 0.07692 BC019038 gi|17512114|gb|BC019038.1BC019038 6.6E−289 Homo sapiens, small nuclear RNA activating complex, polypeptide 1, 43 kD, clone MGC: 20773 IMAGE: 45 3426 I:1805613:01B01:G03 MA105:G03 U79725 gi|1814276|gb|U79725.1HSU79725 5.4E−202 Human A33 antigen precursor mRNA, complete cds 3427 I:1524885:01A01:H03 MA103:H03 Y12065 gi|2230877|emb|Y12065.1HSNOP56 0 Homo sapiens mRNA for nucleolar protein hNop56 3428 I:2888464:01B01:H03 MA105:H03 S73591 gi|688296|gb|S73591.1S73591 Homo 1.7E−267 sapiens brain-expressed HHCPA78 homolog VDUP1 (Gene) mRNA, complete cds 3429 I:1992788:04B01:B03 MA117:B03 AL161985 gi|7328121|emb|AL161985.1HSM802609 0 Homo sapiens mRNA; cDNA DKFZp761J1810 (from clone DKFZp761J1810) 3430 I:1413451:04A01:F03 MA115:F03 D88648 gi|2653566|dbj|D88648.1D88648 Homo 4.1E−184 sapiens mRNA for B-FABP, complete cds 3431 I:2779515:04B01:C09 MA117:C09 AL136543 gi|6807646|emb|AL136543.1HSM801517 2.2E−285 Homo sapiens mRNA; cDNA DKFZp761K0511 (from clone DKFZp761K0511); partial cds 3432 I:1583076:02B01:G09 MA109:G09 NM_000669 gi|11496888|ref|NM_000669.2 Homo   6E−261 sapiens alcohol dehydrogenase 1C (class I), gamma polypeptide (ADH1C), mRNA 3433 I:3070110:05A02:B03 MA120:B03 AF061016 gi|3127126|gb|AF061016.1AF061016 6.4E−295 Homo sapiens UDP-glucose dehydrogenase (UGDH) mRNA, complete cds 3434 I:1904493:05A02:H03 MA120:H03 Z22555 gi|397606|emb|Z22555.1HSCLA1GNA 9.7E−229 H. sapiens encoding CLA-1 mRNA 3435 I:2860815:05A02:A09 MA120:A09 AF067420 gi|3201899|gb|AF067420.1AF067420 1.7E−100 Homo sapiens SNC73 protein (SNC73) mRNA, complete cds 3436 I:1930135:07A02:G03 MA128:G03 3437 I:3747901:06B02:G03 MA126:G03 BC004979 gi|13436403|gb|BC004979.1BC004979 1.6E−289 Homo sapiens, clone MGC: 3855 IMAGE: 2905681, mRNA, complete cds 3438 I:1720946:06A02:A09 MA124:A09 BC010733 gi|14789594|gb|BC010733.1BC010733 1.1E−296 Homo sapiens, clone IMAGE: 3897044, mRNA, partial cds 3439 I:2877413:06B02:D09 MA126:D09 BC000700 gi|12653822|gb|BC000700.1BC000700 5.5E−255 Homo sapiens, clone MGC: 3101 IMAGE: 3350198, mRNA, complete cds 3440 I:3035279:06B02:E09 MA126:E09 BC001125 gi|12654578|gb|BC001125.1BC001125   2E−276 Homo sapiens, peptidylprolyl isomerase B (cyclophilin B), clone MGC: 2224 IMAGE: 2966791, mRNA, com 3441 I:2503913:03A02:E09 MA112:E09 BC010952 gi|15012094|gb|BC010952.1BC010952 1.5E−261 Homo sapiens, Similar to protease inhibitor 3, skin-derived (SKALP), clone MGC: 13613 IMAGE: 408315 3442 I:1517380:01A02:B03 MA104:B03 AB033032 gi|6330486|dbj|AB033032.1AB033032 1.2E−277 Homo sapiens mRNA for KIAA1206 protein, partial cds 3443 I:3138128:01B02:C03 MA106:C03 D31887 gi|505101|dbj|D31887.1HUMORFKG1P   1E−300 Human mRNA for KIAA0062 gene, partial cds 3444 I:2453722:01A02:E03 MA104:E03 BC003582 gi|13097770|gb|BC003582.1BC003582   1E−300 Homo sapiens, polymerase (RNA) II (DNA directed) polypeptide F, clone MGC: 2669 IMAGE: 3546712, mRN 3445 I:1414260:01A02:A09 MA104:A09 AB002318 gi|2224580|dbj|AB002318.1AB002318 3.4E−284 Human mRNA for KIAA0320 gene, partial cds 3446 I:2891247:01B02:A09 MA106:A09 D43638 gi|940399|dbj|D43638.1HUMMTG8AP 8.4E−151 Human mRNA for MTG8a protein, complete cds 3447 I:1682176:01A02:F09 MA104:F09 U78556 gi|1688306|gb|U78556.1HSU78556   1E−293 Human cisplatin resistance associated alpha protein (hCRA alpha) mRNA, complete cds 3448 I:2739076:04A02:D03 MA116:D03 NM_001023 gi|14591915|ref|NM_001023.2 Homo 2.1E−248 sapiens ribosomal protein S20 (RPS20), mRNA 3449 I:1900378:04B02:F03 MA118:F03 AB002363 gi|2224670|dbj|AB002363.1AB002363 3.1E−275 Human mRNA for KIAA0365 gene, partial cds 3450 I:1603391:04A02:G03 MA116:G03 AF036874 gi|9738910|gb|AF036874.1AF036874 3.7E−275 Homo sapiens multiple endocrine neoplasia type 1 candidate protein number 18 (HSPF2) mRNA, complet 3451 I:2018222:04A02:C09 MA116:C09 BC008795 gi|14250659|gb|BC008795.1BC008795   2E−192 Homo sapiens, proteasome (prosome, macropain) subunit, beta type, 9 (large multifunctional protea 3452 I:1327263:04A02:F09 MA116:F09 M25629 gi|186652|gb|M25629.1HUMKALX 1.4E−283 Human kallikrein mRNA, complete cds, clone clone phKK25 3453 I:1734393:02A02:B09 MA108:B09 X73502 gi|406853|emb|X73502.1HSENCY20 H. Sapiens 0 mRNA for cytokeratin 20 3454 I:2190607:02A02:E09 MA108:E09 BC008012 gi|14124971|gb|BC008012.1BC008012 3.5E−244 Homo sapiens, eukaryotic translation elongation factor 1 delta (guanine nucleotide exchange prote 3455 I:2447969:08A01:E04 MA131:E04 0.16896 3456 I:1753033:08B01:H10 MA133:H10 AL359055 gi|8518180|emb|AL359055.1IR2344436 9.6E−24 Homo sapiens mRNA full length insert cDNA clone EUROIMAGE 2344436 3457 I:2456393:07B01:E10 MA129:E10 BC005029 gi|13477142|gb|BC005029.1BC005029 3.6E−259 Homo sapiens, hypothetical protein FLJ10718, clone MGC: 12594 IMAGE: 4040181, mRNA, complete cds 3458 I:1719920:06B01:A04 MA125:A04 0.13978 BC001903 gi|12804902|gb|BC001903.1BC001903 1.4E−274 Homo sapiens, Similar to interleukin 10 receptor, beta, clone MGC: 2210 IMAGE: 3544611, mRNA, compl 3459 I:2927362:06B01:H04 MA125:H04 BC019336 gi|17939560|gb|BC019336.1BC019336 0 Homo sapiens, clone IMAGE: 3617778, mRNA, partial cds 3460 I:4082816:06B01:F10 MA125:F10 BC001365 gi|12655034|gb|BC001365.1BC001365 6.1E−230 Homo sapiens, ribosomal protein L4, clone MGC: 2201 IMAGE: 3051487, mRNA, complete cds 3461 I:1803446:03A01:A04 MA111:A04 BC000062 gi|12652632|gb|BC000062.1BC000062   1E−300 Homo sapiens, solute carrier family 1 (neutral amino acid transporter), member 5, clone MGC: 1387 3462 I:1557490:03A01:C04 MA111:C04 BC003560 gi|13097707|gb|BC003560.1BC003560 0 Homo sapiens, ribophorin II, clone MGC: 1817 IMAGE: 3546673, mRNA, complete cds 3463 I:1445895:03B01:E10 MA113:E10 BC009196 gi|14327943|gb|BC009196.1BC009196 3.6E−131 Homo sapiens, phosphatidic acid phosphatase type 2B, clone MGC: 15306 IMAGE: 3960223, mRNA, complet 3464 I:1336836:01A01:H04 MA103:H04 M32215 gi|307524|gb|M32215.1HUMTSHRX   1E−300 Human thyroid stimulatory hormone receptor (TSHR) mRNA, complete cds 3465 I:1802745:01B01:E10 MA105:E10 D42087 gi|576555|dbj|D42087.1HUMHA0793A 8.4E−279 Human mRNA for KIAA0118 gene, partial cds 3466 I:2503003:01B01:H10 MA105:H10 AF020352 gi|2655054|gb|AF020352.1AF020352 1.4E−255 Homo sapiens NADH: ubiquinone oxidoreductase 15 kDa IP subunit mRNA, nuclear gene encoding mitochon 3467 I:1655377:10A01:F04 MA64:F04 AK000706 gi|7020960|dbj|AK000706.1AK000706 2.7E−210 Homo sapiens cDNA FLJ20699 fis, clone KAIA2372 3468 I:1430662:04A01:A04 MA115:A04 AF078035 gi|4322303|gb|AF078035.1AF078035 3.9E−262 Homo sapiens translation initiation factor IF2 mRNA, complete cds 3469 I:3335055:04A01:G04 MA115:G04 BC004390 gi|13325149|gb|BC004390.1BC004390 3.7E−181 Homo sapiens, phosphatidylserine synthase 1, clone MGC: 10968 IMAGE: 3634879, mRNA, complete cds 3470 I:2457671:04B01:B10 MA117:B10 BC000469 gi|12653398|gb|BC000469.1BC000469 4.3E−299 Homo sapiens, eukaryotic translation initiation factor 3, subunit 7 (zeta, 66/67 kD), clone MGC: 85 3471 I:1641421:02A01:C10 MA107:C10 S69369 gi|545844|gb|S69369.1S69369 1.5E−180 PAX3A = transcription factor [human, adult cerebellum, mRNA, 1248 nt] 3472 I:1655225:02B01:E10 MA109:E10 AB002331 gi|2224606|dbj|AB002331.1AB002331 7.1E−273 Human mRNA for KIAA0333 gene, partial cds 3473 I:1313325:05A02:B04 MA120:B04 U09550 gi|1184036|gb|U09550.1HSU09550 5.2E−283 Human oviductal glycoprotein mRNA, complete cds 3474 I:1558081:05B02:A10 MA122:A10 NM_004530 gi|11342665|ref|NM_004530.1 Homo 0 sapiens matrix metalloproteinase 2 (gelatinase A, 72 kD gelatinase, 72 kD type IV collagenase) (MMP2 3475 I:1889191:05A02:H10 MA120:H10 BC001619 gi|12804426|gb|BC001619.1BC001619 1.1E−299 Homo sapiens, Similar to aldehyde dehydrogenase 5, clone MGC: 2230 IMAGE: 3356389, mRNA, complete c 3476 I:3495906:07A02:C10 MA128:C10 U19251 gi|2642132|gb|U19251.1HSU19251 Homo 0 sapiens neuronal apoptosis inhibitory protein mRNA, complete cds 3477 I:3704132:03A02:D10 MA112:D10 Z49194 gi|974830|emb|Z49194.1HSOBF1 1.3E−102 H. sapiens mRNA for oct-binding factor 3478 I:1636553:03B02:F10 MA114:F10 AB001895 gi|2588990|dbj|AB001895.1AB001895 2.8E−130 Homo sapiens mRNA for B120, complete cds 3479 I:1402228:03B02:H10 MA114:H10 BC008588 gi|14250316|gb|BC008588.1BC008588 7.8E−170 Homo sapiens, Similar to plastin 3 (T isoform), clone IMAGE: 3447893, mRNA, partial cds 3480 I:1361963:01A02:B04 MA104:B04 L13616 gi|439874|gb|L13616.1HUMFAKX 2.4E−291 Human focal adhesion kinase (FAK) mRNA, complete cds 3481 I:1510424:01A02:D04 MA104:D04 X04481 gi|34627|emb|X04481.1HSMH3C2R   1E−300 Human mRNA for complement component C2 3482 I:2918558:01B02:D04 MA106:D04 AF000994 gi|2580573|gb|AF000994.1HSAF000994 8.8E−285 Homo sapiens ubiquitous TPR motif, Y isoform (UTY) mRNA, alternative transcript 3, complete cds 3483 I:1731061:01A02:D10 MA104:D10 BC000418 gi|12653298|gb|BC000418.1BC000418   1E−300 Homo sapiens, ectodermal-neural cortex (with BTB-like domain), clone MGC: 8659 IMAGE: 2964376, mRNA 3484 I:2579602:04A02:A04 MA116:A04 BC005128 gi|13477308|gb|BC005128.1BC005128   1E−300 Homo sapiens, ribosomal protein L7a, clone MGC: 10607 IMAGE: 3938260, mRNA, complete cds 3485 I:2824181:04B02:A04 MA118:A04 BC004900 gi|13436172|gb|BC004900.1BC004900   1E−300 Homo sapiens, ribosomal protein L13a, clone IMAGE: 3545758, mRNA, partial cds 3486 I:2123183:04A02:B04 MA116:B04 BC001164 gi|12654652|gb|BC001164.1BC001164 2.1E−198 Homo sapiens, proteasome (prosome, macropain) 26S subunit, non-ATPase, 8, clone MGC: 1660 IMAGE: 35 3487 I:1958560:04A02:C10 MA116:C10 0.0522 BC016147 gi|16359382|gb|BC016147.1BC016147 1.5E−277 Homo sapiens, clone MGC: 9485 IMAGE: 3921259, mRNA, complete cds 3488 I:1447903:04A02:G10 MA116:G10 AK056274 gi|16551627|dbj|AK056274.1AK056274 2.2E−48 Homo sapiens cDNA FLJ31712 fis, clone NT2RI2006445, moderately similar to INSULIN-LIKE GROWTH FA 3489 I:1875576:02A02:E10 MA108:E10 U04897 gi|451563|gb|U04897.1HSU04897 Human 1.1E−140 orphan hormone nuclear receptor RORalpha1 mRNA, complete cds 3490 I:1709457:02B02:G10 MA110:G10 X65873 gi|34082|emb|X65873.1HSKHCMR 0 H. sapiens mRNA for kinesin (heavy chain) 3491 I:2155675:08B01:G05 MA133:G05 0.83871 3492 I:1635069:07A01:A05 MA127:A05 D15049 gi|475003|dbj|D15049.1HUMSAP1C 3.5E−197 Homo sapiens mRNA for protein tyrosine phosphatase precursor, complete cds 3493 I:1453445:07A01:G05 MA127:G05 0.07788 BC001784 gi|13937607|gb|BC001784.1BC001784 1.2E−265 Homo sapiens, Similar to acidic 82 kDa protein mRNA, clone IMAGE: 3542384, mRNA 3494 I:3002566:07A01:D11 MA127:D11 D26350 gi|450468|dbj|D26350.1HUMHT2I Human 0 mRNA for type 2 inositol 1,4,5- trisphosphate receptor, complete cds 3495 I:1631511:06A01:C05 MA123:C05 BC001454 gi|12655192|gb|BC001454.1BC001454 0 Homo sapiens, phosphoenolpyruvate carboxykinase 2 (mitochondrial), clone MGC: 1492 IMAGE: 3138368, 3496 I:1610523:06A01:H05 MA123:H05 L19183 gi|307154|gb|L19183.1HUMMAC30X 0 Human MAC30 mRNA, 3′ end 3497 I:3297656:06B01:E11 MA125:E11 D14530 gi|414348|dbj|D14530.1HUMRSPT   5E−277 Human homolog of yeast ribosomal protein S28, complete cds 3498 I:2509730:06B01:H11 MA125:H11 X91788 gi|1001874|emb|X91788.1HSICLNGEN 0 H. sapiens mRNA for Icln protein 3499 I:2121863:03B01:D05 MA113:D05 BC002738 gi|12803796|gb|BC002738.1BC002738 6.9E−47 Homo sapiens, cysteine-rich protein 1 (intestinal), clone MGC: 3888 IMAGE: 3631097, mRNA, complete 3500 I:1413704:03B01:E05 MA113:E05 NM_003903 gi|14110370|ref|NM_003903.2 Homo 8.5E−254 sapiens CDC16 cell division cycle 16 homolog (S. cerevisiae) (CDC16), mRNA 3501 I:1626232:03A01:A11 MA111:A11 AF048700 gi|2935439|gb|AF048700.1AF048700 3.5E−203 Homo sapiens gastrointestinal peptide (PEC-60) mRNA, complete cds 3502 I:2354446:01B01:B05 MA105:B05 AF131913 gi|4928275|gb|AF131913.1AF131913 1.2E−218 Homo sapiens alpha-(1,3/1,4)- fucosyltransferase (FT3B) mRNA, complete cds 3503 I:2916753:01B01:E05 MA105:E05 X62534 gi|32332|emb|X62534.1HSHMG2 3.9E−179 H. sapiens HMG-2 mRNA 3504 I:2555034:01A01:A11 MA103:A11 0.09272 U39196 gi|1055027|gb|U39196.1HSU39196 9.4E−151 Human clone hGIRK1 G-protein coupled inwardly rectifying potassium channel mRNA, complete cds 3505 I:2804190:01B01:D11 MA105:D11 BC004300 gi|13279166|gb|BC004300.1BC004300 2.8E−166 Homo sapiens, Similar to villin-like, clone MGC: 10896 IMAGE: 3622951, mRNA, complete cds 3506 I:1814488:01A01:E11 MA103:E11 AF044773 gi|3002950|gb|AF044773.1AF044773 8.8E−208 Homo sapiens breakpoint cluster region protein 1 (BCRG1) mRNA, complete cds 3507 I:2474163:01B01:E11 MA105:E11 J03037 gi|179771|gb|J03037.1HUMCAIIA Human 1.2E−143 carbonic anhydrase II mRNA, complete cds 3508 I:1402967:01A01:G11 MA103:G11 Y00651 gi|34504|emb|Y00651.1HSMCP Human 1.5E−227 mRNA for membrane cofactor protein 3509 I:2821541:10A01:D11 MA64:D11 0.356 3510 I:2888814:04B01:A05 MA117:A05 Y10806 gi|1808645|emb|Y10806.1HSY10806   1E−300 H. sapiens mRNA for arginine methyltransferase, splice variant, 1316 bp 3511 I:1451005:04A01:C05 MA115:C05 BC001771 gi|12804688|gb|BC001771.1BC001771 3.3E−200 Homo sapiens, general transcription factor IIF, polypeptide 2 (30 kD subunit), clone MGC: 1502 IMAG 3512 I:1457726:04A01:H05 MA115:H05 AK001686 gi|7023098|dbj|AK001686.1AK001686 3.9E−209 Homo sapiens cDNA FLJ10824 fis, clone NT2RP4001086 3513 I:2883195:04B01:H05 MA117:H05 BC000672 gi|12653772|gb|BC000672.1BC000672   1E−290 Homo sapiens, guanine nucleotide binding protein (G protein), beta polypeptide 2-like 1, clone MG 3514 I:1603605:04A01:G11 MA115:G11 0.04363 D38305 gi|1580723|dbj|D38305.1HUMTOB 1.3E−268 Human mRNA for Tob, complete cds 3515 I:2832224:04A01:H11 MA115:H11 L09604 gi|177899|gb|L09604.1HUMA4 Homo 0 sapiens differentiation-dependent A4 protein mRNA, complete cds 3516 I:2231364:02A01:A05 MA107:A05 D87469 gi|1665820|dbj|D87469.1D87469 Human 0 mRNA for KIAA0279 gene, partial cds 3517 I:1595081:02B01:F11 MA109:F11 S36219 gi|249623|gb|S36219.1S36219   1E−300 prostaglandin G/H synthase {alternative splicing product} [human, lung fibroblast, clone HCO-T9, mRNA, 3518 I:1877913:05B02:C05 MA122:C05 U51903 gi|1262925|gb|U51903.1HSU51903   1E−300 Human RasGAP-related protein (IQGAP2) mRNA, complete cds 3519 I:1666130:05B02:F05 MA122:F05 X05790 gi|28535|emb|X05790.1HSAGALAR 0 Human mRNA for alpha-galactosidase A (EC 3.2.1-22) 3520 I:1709995:05B02:H05 MA122:H05 U78525 gi|2558667|gb|U78525.1HSU78525 Homo 8.3E−279 sapiens eukaryotic translation initiation factor (eIF3) mRNA, complete cds 3521 I:3872557:07A02:B05 MA128:B05 NM_000518 gi|13788565|ref|NM_000518.3 Homo 0 sapiens hemoglobin, beta (HBB), mRNA 3522 I:2734906:07A02:E11 MA128:E11 NM_001997 gi|17981709|ref|NM_001997.2 Homo 1.3E−277 sapiens Finkel-Biskis-Reilly murine sarcoma virus (FBR-MuSV) ubiquitously expressed (fox derived); 3523 I:1798585:06A02:B05 MA124:B05 BC008767 gi|14250615|gb|BC008767.1BC008767 0 Homo sapiens, Similar to acyl-Coenzyme A oxidase 1, palmitoyl, clone MGC: 1198 IMAGE: 3051501, mRNA 3524 I:1683389:06A02:F05 MA124:F05 BC015335 gi|15929831|gb|BC015335.1BC015335 0 Homo sapiens, immature colon carcinoma transcript 1, clone MGC: 21251 IMAGE: 4418983, mRNA, complet 3525 I:1704517:06A02:G05 MA124:G05 BC005820 gi|14710649|gb|BC005820.1BC005820 0 Homo sapiens, clone IMAGE: 3937549, mRNA 3526 I:2792982:06B02:H05 MA126:H05 X71345 gi|405755|emb|X71345.1HSTRYIVB 0 H. sapiens mRNA for trypsinogen IV b- form 3527 I:3511355:06B02:D11 MA126:D11 NM_001002 gi|16933547|ref|NM_001002.2 Homo   1E−300 sapiens ribosomal protein, large, P0 (RPLP0), transcript variant 1, mRNA 3528 I:1738060:03A02:A05 MA112:A05 BC000508 gi|12653472|gb|BC000508.1BC000508 1.1E−243 Homo sapiens, proteasome (prosome, macropain) subunit, beta type, 1, clone MGC: 8505 IMAGE: 2822268 3529 I:1810821:03B02:B05 MA114:B05 BC016956 gi|16877417|gb|BC016956.1BC016956   7E−217 Homo sapiens, clone MGC: 21520 IMAGE: 3900854, mRNA, complete cds 3530 I:2451279:03A02:E05 MA112:E05 BC009868 gi|14602690|gb|BC009868.1BC009868 1.8E−167 Homo sapiens, replication protein A3 (14 kD), clone MGC: 16404 IMAGE: 3940438, mRNA, complete cds 3531 I:1431166:03B02:E05 MA114:E05 BC010444 gi|14714612|gb|BC010444.1BC010444 5.5E−230 Homo sapiens, matrilin 2, clone MGC: 17281 IMAGE: 4215380, mRNA, complete cds 3532 I:2949427:03B02:A11 MA114:A11 BC006794 gi|13905021|gb|BC006794.1BC006794 3.2E−225 Homo sapiens, Similar to interferon induced transmembrane protein 3 (1-8U), clone MGC: 5225 IMAGE: 3533 I:1458366:03B02:E11 MA114:E11 AF009202 gi|2454507|gb|AF009202.1AF009202 3.7E−290 Homo sapiens YAC clone 136A2 unknown mRNA, 3′untranslated region 3534 I:1525881:03B02:G11 MA114:G11 AF368463 gi|14583005|gb|AF368463.1AF368463 8.5E−176 Homo sapiens carboxypeptidase M mRNA, complete cds 3535 I:2071473:01A02:E05 MA104:E05 X17567 gi|36512|emb|X17567.1HSSNRNPB 0 H. sapiens RNA for snRNP protein B 3536 I:2481012:01A02:C11 MA104:C11 BC001625 gi|12804436|gb|BC001625.1BC001625 1.6E−236 Homo sapiens, Similar to for protein disulfide isomerase-related, clone MGC: 1259 IMAGE: 3537659, m 3537 I:2816931:01B02:C11 MA106:C11 D88827 gi|2342505|dbj|D88827.1D88827 Homo 4.2E−159 sapiens mRNA for zinc finger protein FPM315, complete cds 3538 I:1806769:01B02:F11 MA106:F11 NM_005971 gi|11612675|ref|NM_005971.2 Homo 8.8E−242 sapiens FXYD domain-containing ion transport regulator 3 (FXYD3), transcript variant 1, mRNA 3539 I:2636634:04B02:A11 MA118:A11 L32137 gi|602449|gb|L32137.1HUMCOMP 2.5E−210 Human germline oligomeric matrix protein (COMP) mRNA, complete cds 3540 I:1649959:02B02:E11 MA110:E11 BC002700 gi|12803726|gb|BC002700.1BC002700 2.5E−254 Homo sapiens, Similar to keratin 7, clone MGC: 3625 IMAGE: 3610347, mRNA, complete cds 3541 I:1633719:02B02:F11 MA110:F11 J05428 gi|340079|gb|J05428.1HUMUDPGTA 3.8E−290 Human 3,4-catechol estrogen UDP- glucuronosyltransferase mRNA, complete cds 3542 I:1901035:02B02:G11 MA110:G11 AF081513 gi|5725637|gb|AF081513.1AF081513 1.2E−143 Homo sapiens TGF-beta type secreted signaling protein LEFTYA mRNA, complete cds 3543 I:2503879:08B01:C12 MA133:C12 AF150733 gi|7688664|gb|AF150733.1AF150733 3.9E−237 Homo sapiens AD-014 protein mRNA, complete cds 3544 I:2383065:07B01:B06 MA129:B06 AJ335311 gi|15879729|emb|AJ335311.1HSA335311 3.7E−50 Homo sapiens genomic sequence surrounding NotI site, clone NR1-WB8C 3545 I:3357245:07A01:F06 MA127:F06 X95073 gi|2879814|emb|X95073.1HSTRAXGEN 0 H. sapiens mRNA for translin associated protein X 3546 I:2832314:07A01:G06 MA127:G06 M26252 gi|338826|gb|M26252.1HUMTCBA 7.8E−279 Human TCB gene encoding cytosolic thyroid hormone-binding protein, complete cds 3547 I:3667096:07A01:D12 MA127:D12 BC003412 gi|13097323|gb|BC003412.1BC003412   1E−300 Homo sapiens, cyclophilin, clone MGC: 5016 IMAGE: 3451034, mRNA, complete cds 3548 I:1798283:06A01:D06 MA123:D06 BC016835 gi|16877126|gb|BC016835.1BC016835   1E−300 Homo sapiens, Similar to synaptophysin- like protein, clone MGC: 10011 IMAGE: 3883697, mRNA, complet 3549 I:1648206:03A01:B06 MA111:B06 AJ420535 gi|17066399|emb|AJ420535.1HSA420535 6.2E−264 Homo sapiens mRNA full length insert cDNA clone EUROIMAGE 993611 3550 I:3360476:03B01:B12 MA113:B12 Y08768 gi|1877211|emb|Y08768.1HSIL13 1.4E−177 H. sapiens mRNA for IL-13 receptor 3551 I:2500511:03B01:C12 MA113:C12 AJ001531 gi|2661423|emb|AJ001531.1HSNEUROTR 3.9E−265 Homo sapiens mRNA for neurotrypsin 3552 I:1730806:03B01:D12 MA113:D12 AL049705 gi|4678821|emb|AL049705.1HS262D122 7.8E−220 Human gene from PAC 262D12, chromosome 1 3553 I:2479074:01B01:C06 MA105:C06 AF096304 gi|4191395|gb|AF096304.1AF096304 0 Homo sapiens putative sterol reductase SR-1 (TM7SF2) mRNA, complete cds 3554 I:1635004:01B01:E06 MA105:E06 BC003661 gi|13177786|gb|BC003661.1BC003661 4.6E−231 Homo sapiens, lectin, galactoside-binding, soluble, 4 (galectin 4), clone MGC: 698 IMAGE: 2967411, 3555 I:2378569:01B01:G06 MA105:G06 BC000341 gi|12653146|gb|BC000341.1BC000341 8.7E−236 Homo sapiens, signal sequence receptor, beta (translocon-associated protein beta), clone MGC: 8566 3556 I:2207849:01A01:D12 MA103:D12 X65019 gi|33792|emb|X65019.1HSIL1BRNA 0 H. sapiens mRNA for interleukin-1B converting enzyme 3557 I:1504554:01A01:F12 MA103:F12 0.1646 U43843 gi|1532120|gb|U43843.1HSU43843 4.6E−151 Human h-neuro-d4 protein mRNA, complete cds 3558 I:2989991:04B01:A06 MA117:A06 AF400442 gi|15217078|gb|AF400442.1AF400442   1E−300 Homo sapiens pigment epithelium-derived factor (SERPINF1) mRNA, complete cds 3559 I:2852561:04B01:B06 MA117:B06 J02769 gi|177206|gb|J02769.1HUM4F2A Human 1.4E−255 4F2 antigen heavy chain mRNA, complete cds 3560 I:2832839:04A01:C12 MA115:C12 NM_006399 gi|5453562|ref|NM_006399.1 Homo 2.6E−138 sapiens basic leucine zipper transcription factor, ATF-like (BATF), mRNA 3561 I:2845548:04B01:E12 MA117:E12 AY034482 gi|15809587|gb|AY034482.1 Homo 3.1E−278 sapiens hnRNP Q2 mRNA, complete cds 3562 I:1251819:02B01:B06 MA109:B06 X78669 gi|469884|emb|X78669.1HSERC55R 9.1E−288 H. sapiens ERC-55 mRNA 3563 I:1672930:02B01:D06 MA109:D06 X83617 gi|620082|emb|X83617.1HSRANBP1 4.7E−274 H. sapiens mRNA for RanBP1 3564 I:2122820:02B01:E06 MA109:E06 BC001738 gi|12804628|gb|BC001738.1BC001738 3.9E−234 Homo sapiens, Similar to ubiquitin- conjugating enzyme E2G 2 (homologous to yeast UBC7), clone MGC 3565 I:2174920:02A01:H06 MA107:H06 BC006230 gi|13623260|gb|BC006230.1BC006230 9.5E−260 Homo sapiens, lysophospholipase-like, clone MGC: 10338 IMAGE: 3945191, mRNA, complete cds 3566 I:1875994:05B02:E06 MA122:E06 BC002638 gi|12803606|gb|BC002638.1BC002638 2.2E−217 Homo sapiens, hypothetical protein, clone MGC: 3365 IMAGE: 3608062, mRNA, complete cds 3567 I:1858644:05A02:G06 MA120:G06 M55268 gi|177837|gb|M55268.1HUMA1CKII 3.4E−284 Human casein kinase 11 alpha' subunit mRNA, complete cds 3568 I:1700047:06A02:E06 MA124:E06 BC000405 gi|12653272|gb|BC000405.1BC000405 1.4E−224 Homo sapiens, small nuclear ribonucleoprotein polypeptide A, clone MGC: 8567 IMAGE: 2822987, mRNA, 3569 I:1718257:06B02:E06 MA126:E06 AF020760 gi|5870864|gb|AF020760.2AF020760 0 Homo sapiens serine protease (OMI) mRNA, complete cds 3570 I:1612306:06A02:F06 MA124:F06 BC002594 gi|12803530|gb|BC002594.1BC002594 4.5E−271 Homo sapiens, dolichyl- diphosphooligosaccharide-protein glycosyltransferase, clone MGC: 2191 IMAGE 3571 I:1637427:06A02:F12 MA124:F12 U31659 gi|1136305|gb|U31659.1HSU31659 7.5E−217 Human TBP-associated factor TAFII80 mRNA, complete cds 3572 I:2513883:03A02:B12 MA112:B12 X76717 gi|435674|emb|X76717.1HSMT1L 2.1E−142 H. sapiens MT-11 mRNA 3573 I:2645840:01A02:G06 MA104:G06 X97795 gi|1495482|emb|X97795.1HSRAD54 1.7E−295 H. sapiens mRNA homologous to S. cerevisiae RAD54 3574 I:1737403:01A02:A12 MA104:A12 Z29067 gi|479172|emb|Z29067.1HSNEK3R 0 H. sapiens nek3 mRNA for protein kinase 3575 I:1733522:01B02:H12 MA106:H12 BC017880 gi|17389723|gb|BC017880.1BC017880 7.7E−95 Homo sapiens, clone MGC: 22754 IMAGE: 4277855, mRNA, complete cds 3576 RG:160664:10006:E07 MA155:E07 NM_020975 gi|10862702|ref|NM_020975.1 Homo 1.7E−298 sapiens ret proto-oncogene (multiple endocrine neoplasia and medullary thyroid carcinoma 1, Hirsch 3577 I:747335:16A01:E01 MA87:E01 NM_000985 gi|14591906|ref|NM_000985.2 Homo 3.1E−272 sapiens ribosomal protein L17 (RPL17), mRNA 3578 I:2085191:16A01:H01 MA87:H01 M22612 gi|521215|gb|M22612.1HUMTRPSGNA   1E−287 Human pancreatic trypsin 1 (TRY1) mRNA, complete cds 3579 I:1211126:16A01:E07 MA87:E07 Y13901 gi|2832349|emb|Y13901.1HSFGFR4G   1E−300 Homo sapiens FGFR-4 gene 3580 RG:669310:10010:C01 MA159:C01 BC000833 gi|12654054|gb|BC000833.1BC000833 0 Homo sapiens, clone IMAGE: 3455871, mRNA, partial cds 3581 RG:730402:10010:H01 MA159:H01 0.225 BC000633 gi|12653696|gb|BC000633.1BC000633 2.1E−38 Homo sapiens, TTK protein kinase, clone MGC: 865 IMAGE: 3343925, mRNA, complete cds 3582 RG:1047541:10012:C07 MA161:C07 AF156965 gi|5731112|gb|AF156965.1AF156965 0 Homo sapiens translocon-associated protein alpha subunit mRNA, complete cds 3583 RG:1161753:10012:E07 MA161:E07 X12883 gi|30310|emb|X12883.1HSCYKT18 0 Human mRNA for cytokeratin 18 3584 I:1218464:17B01:E01 MA93:E01 0.47248 3585 I:958633:17B01:G07 MA93:G07 AF267862 gi|12006050|gb|AF267862.1AF267862 1.8E−180 Homo sapiens DC44 mRNA, complete cds 3586 I:1602726:09B01:B07 MA137:B07 0.45675 3587 RG:205212:10007:B01 MA156:B01 AF069747 gi|4106379|gb|AF069747.1AF069747 6.1E−227 Homo sapiens MTG8-like protein MTGR1a mRNA, complete cds 3588 RG:207395:10007:B07 MA156:B07 Z74616 gi|1418929|emb|Z74616.1HSPPA2ICO 0 H. sapiens mRNA for prepro-alpha2(I) collagen 3589 I:349535:16B02:G01 MA90:G01 0.19957 3590 I:2323525:16A02:H01 MA88:H01 0.30114 3591 I:1965049:16B02:D07 MA90:D07 AF113007 gi|6642737|gb|AF113007.1AF113007 4.1E−162 Homo sapiens PRO0066 mRNA, complete cds 3592 I:2054436:16A02:G07 MA88:G07 0.15978 3593 RG:1506197:10013:F01 MA162:F01 NM_052841 gi|17017992|ref|NM_052841.2 Homo   2E−137 sapiens serine/threonine kinase 22C (spermiogenesis associated) (STK22C), mRNA 3594 RG:1871436:10015:G01 MA164:G01 X60489 gi|31099|emb|X60489.1HSEF1B Human 0 mRNA for elongation factor-1-beta 3595 RG:1705470:10015:B07 MA164:B07 L38734 gi|769675|gb|L38734.1HUMHTK Homo 2.1E−282 sapiens hepatoma transmembrane kinase ligand (HTK ligand) mRNA, complete cds 3596 I:546910:17B02:B07 MA94:B07 AK002212 gi|7023953|dbj|AK002212.1AK002212 3.3E−97 Homo sapiens cDNA FLJ11350 fis, clone Y79AA1001647 3597 I:1799023:09B02:F01 MA138:F01 AK023003 gi|10434717|dbj|AK023003.1AK023003 2.5E−164 Homo sapiens cDNA FLJ12941 fis, clone NT2RP2005116, moderately similar to PUTATIVE EUKARYOTIC TR 3598 I:2380380:09B02:H01 MA138:H01 AF268037 gi|8745546|gb|AF268037.1AF268037 0 Homo sapiens C8ORF4 protein (C8ORF4) mRNA, complete cds 3599 I:2319269:18A01:F02 MA95:F02 AK022882 gi|10434533|dbj|AK022882.1AK022882 1.1E−206 Homo sapiens cDNA FLJ12820 fis, clone NT2RP2002736 3600 I:2296344:18A01:D08 MA95:D08 AJ387747 gi|6562532|emb|AJ387747.1HSA387747 3.6E−225 Homo sapiens mRNA for sialin 3601 RG:155066:10006:E02 MA155:E02 BC018851 gi|17402989|gb|BC018851.1BC018851 2.2E−279 Homo sapiens, clone IMAGE: 3141444, mRNA 3602 RG:180135:10006:G02 MA155:G02 L37043 gi|852056|gb|L37043.1HUMCSNK1E 0 Homo sapiens casein kinase I epsilon mRNA, complete cds 3603 RG:178093:10006:F08 MA155:F08 AL117430 gi|5911865|emb|AL117430.1HSM800939 0 Homo sapiens mRNA; cDNA DKFZp434D156 (from clone DKFZp434D156); partial cds 3604 RG:184042:10006:G08 MA155:G08 BC017459 gi|16907188|gb|BC017459.1BC017459 5.3E−240 Homo sapiens, clone IMAGE: 4645230, mRNA 3605 I:1741643:16A01:A02 MA87:A02 D38551 gi|1531549|dbj|D38551.1HUMORF005 1.1E−209 Human mRNA for KIAA0078 gene, complete cds 3606 RG:928026:10012:B02 MA161:B02 AL050147 gi|4884153|emb|AL050147.1HSM800223 1.3E−218 Homo sapiens mRNA; cDNA DKFZp586E0820 (from clone DKFZp586E0820); partial cds 3607 RG:1032969:10012:C02 MA161:C02 AF261717 gi|8926204|gb|AF261717.1AF261717 0 Homo sapiens SAR1 (SAR1) mRNA, complete cds 3608 RG:1322660:10012:H02 MA161:H02 L05144 gi|189944|gb|L05144.1HUMPHOCAR 5.3E−283 Homo sapiens (clone lamda-hPEC-3) phosphoenolpyruvate carboxykinase (PCK1) mRNA, complete cds 3609 RG:968474:10012:B08 MA161:B08 Y11339 gi|7576275|emb|Y11339.2HSY11339 1.7E−227 Homo sapiens mRNA for GalNAc alpha-2, 6-sialyltransferase I, long form 3610 RG:1047592:10012:C08 MA161:C08 X05803 gi|34080|emb|X05803.1HSKERUV   1E−300 Human radiated keratinocyte mRNA 266 (keratin-related protein) 3611 I:617750:17B01:E08 MA93:E08 0.19395 3612 I:2808775:09B01:G02 MA137:G02 0.40171 3613 I:966692:18A02:B08 MA96:B08 0.32029 AK055949 gi|16550804|dbj|AK055949.1AK055949 3.7E−123 Homo sapiens cDNA FLJ31387 fis, clone NT2NE1000018, weakly similar to SUPPRESSOR PROTEIN SRP40 3614 RG:209240:10007:C02 MA156:C02 BC001737 gi|12804626|gb|BC001737.1BC001737   3E−192 Homo sapiens, clone IMAGE: 3354010, mRNA, partial cds 3615 RG:223355:10007:D02 MA156:D02 Z11696 gi|23882|emb|Z11696.1HS44KDAP 5.4E−252 H. sapiens 44 kDa protein kinase related to rat ERK1 3616 RG:267629:10007:H02 MA156:H02 U73824 gi|1857236|gb|U73824.1HSU73824 3.2E−269 Human p97 mRNA, complete cds 3617 I:2246234:16B02:C08 MA90:C08 3618 RG:1696513:10015:B02 MA164:B02 0.07275 AF377330 gi|14278713|gb|AF377330.2AF377330 0 Homo sapiens urokinase-type plasminogen activator (PLAU) gene, complete cds 3619 RG:1733895:10015:D02 MA164:D02 BC009470 gi|14495716|gb|BC009470.1BC009470 0 Homo sapiens, protein kinase, interferon- inducible double stranded RNA dependent activator, clone 3620 RG:1353930:10013:A08 MA162:A08 U86453 gi|2317893|gb|U86453.1HSU86453 6.4E−295 Human phosphatidylinositol 3-kinase catalytic subunit p110delta mRNA, complete cds 3621 RG:1881947:10015:G08 MA164:G08 BC005858 gi|13543399|gb|BC005858.1BC005858 0 Homo sapiens, clone MGC: 3255 IMAGE: 3506187, mRNA, complete cds 3622 RG:166575:10006:F03 MA155:F03 AK057849 gi|16553810|dbj|AK057849.1AK057849   1E−300 Homo sapiens cDNA FLJ25120 fis, clone CBR06020 3623 I:1998994:16A01:A03 MA87:A03 J04205 gi|178686|gb|J04205.1HUMANTLAA 1.6E−258 Human La protein mRNA, complete cds 3624 I:1953051:16A01:D03 MA87:D03 BC004138 gi|13278716|gb|BC004138.1BC004138   2E−276 Homo sapiens, ribosomal protein L6, clone MGC: 1635 IMAGE: 2823733, mRNA, complete cds 3625 I:518826:16A01:E03 MA87:E03 BC007771 gi|14043585|gb|BC007771.1BC007771 2.8E−266 Homo sapiens, dual specificity phosphatase 2, clone MGC: 12703 IMAGE: 4297852, mRNA, complete cds 3626 I:81490:16A01:B09 MA87:B09 BC007942 gi|14044027|gb|BC007942.1BC007942 1.9E−270 Homo sapiens, nucleolar autoantigen (55 kD) similar to rat synaptonemal complex protein, clone MGC 3627 RG:1256163:10012:F03 MA161:F03 M36501 gi|177871|gb|M36501.1HUMA2MGL   1E−300 Human alpha-2-macroglobulin mRNA, 3′ end 3628 RG:1132085:10012:D09 MA161:D09 BC006510 gi|13676353|gb|BC006510.1BC006510 0 Homo sapiens, Similar to cyclin B1, related sequence 1, clone MGC: 2548 IMAGE: 2963100, mRNA, compl 3629 I:2132717:17B01:C09 MA93:C09 AB058749 gi|14017908|dbj|AB058749.1AB058749 3.8E−256 Homo sapiens mRNA for KIAA1846 protein, partial cds 3630 I:1998428:17B01:F09 MA93:F09 AF115926 gi|17998664|gb|AF115926.1AF115926 6.9E−208 Homo sapiens XAG-2 homolog long protein (HPC8) mRNA, complete cds 3631 RG:206694:10007:B03 MA156:B03 X00588 gi|31113|emb|X00588.1HSEGFPRE   1E−300 Human mRNA for precursor of epidermal growth factor receptor 3632 RG:261714:10007:F09 MA156:F09 AF116618 gi|7959738|gb|AF116618.1AF116618 0 Homo sapiens PRO1038 mRNA, complete cds 3633 I:1461515:16A02:C03 MA88:C03 0.3525 3634 I:338859:16A02:H03 MA88:H03 0.27273 3635 I:1425861:16A02:G09 MA88:G09 0.4929 3636 I:1928644:16B02:H09 MA90:H09 0.34967 AK055711 gi|16550506|dbj|AK055711.1AK055711 7.1E−131 Homo sapiens cDNA FLJ31149 fis, clone IMR322001491, moderately similar to Rattus norvegicus tric 3637 RG:1404414:10013:C03 MA162:C03 U01038 gi|393016|gb|U01038.1HSU01038 Human 6.5E−277 pLK mRNA, complete cds 3638 RG:1415437:10013:D03 MA162:D03 BG001190 gi|12654700|gb|BC001190.1BC001190 0 Homo sapiens, Similar to creatine kinase, brain, clone MGC: 3160 IMAGE: 3354679, mRNA, complete cds 3639 RG:1734353:10015:D03 MA164:D03 BC002555 gi|12803460|gb|BC002555.1BC002555 0 Homo sapiens, CDC-like kinase 3, clone MGC: 1777 IMAGE: 3138580, mRNA, complete cds 3640 RG:1872251:10015:G03 MA164:G03 Y17151 gi|4826562|emb|Y17151.2HSY17151 1.7E−31 Homo sapiens mRNA for multidrug resistance protein 3 (ABCC3) 3641 RG:1354408:10013:A09 MA162:A09 AF257466 gi|8453155|gb|AF257466.1AF257466 3.7E−290 Homo sapiens N-acetylneuraminic acid phosphate synthase mRNA, complete cds 3642 RG:1690198:10015:A09 MA164:A09 X90563 gi|1480099|emb|X90563.1HSPPARGAM 0 H. sapiens mRNA for peroxisome proliferactor activated receptor gamma 3643 RG:1476452:10013:E09 MA162:E09 BC007276 gi|13938296|gb|BC007276.1BC007276   1E−300 Homo sapiens, Similar to heat shock cognate 71-kd protein, clone MGC: 15597 IMAGE: 3162067, mRNA, c 3644 I:2069305:09B02:F03 MA138:F03 BC015139 gi|15929410|gb|BC015139.1BC015139 0 Homo sapiens, clone IMAGE: 4040789, mRNA, partial cds 3645 I:1966067:18B01:H04 MA97:H04 AF062916 gi|3941523|gb|AF062916.1AF062916 3.6E−22 Arabidopsis thaliana putative transcription factor (MYB92) mRNA, complete cds 3646 I:2128547:18B01:A10 MA97:A10 AF151839 gi|4929630|gb|AF151839.1AF151839 4.6E−268 Homo sapiens CGI-81 protein mRNA, complete cds 3647 RG:149960:10006:D04 MA155:D04 BC017483 gi|17028354|gb|BC017483.1BC017483 3.9E−237 Homo sapiens, clone IMAGE: 3506553, mRNA 3648 RG:171569:10006:F04 MA155:F04 M64174 gi|190734|gb|M64174.1HUMPTKJAK1   1E−300 Human protein-tyrosine kinase (JAK1) mRNA, complete cds 3649 RG:178638:10006:F10 MA155:F10 BC004408 gi|13325179|gb|BC004408.1BC004408 1.1E−225 Homo sapiens, Similar to high-mobility group 20B, clone MGC: 11001 IMAGE: 3638942, mRNA, complete c 3650 RG:195122:10006:H10 MA155:H10 Z11695 gi|23878|emb|Z11695.1HS40KDAP 4.3E−271 H. sapiens 40 kDa protein kinase related to rat ERK2 3651 I:814216:16A01:F10 MA87:F10 BC006395 gi|13623564|gb|BC006395.1BC006395 9.3E−254 Homo sapiens, cell division cycle 25B, clone MGC: 12797 IMAGE: 4135465, mRNA, complete cds 3652 RG:491163:10010:A04 MA159:A04 BC008767 gi|14250615|gb|BC008767.1BC008767 9.3E−232 Homo sapiens, Similar to acyl-Coenzyme A oxidase 1, palmitoyl, clone MGC: 1198 IMAGE: 3051501, mRNA 3653 RG:827185:10012:A04 MA161:A04 AK055642 gi|16550422|dbj|AK055642.1AK055642 2.5E−251 Homo sapiens cDNA FLJ31080 fis, clone HSYRA2001615, highly similar to Sus scrofa calcium/calmodu 3654 RG:1129102:10012:D04 MA161:D04 NM_000975 gi|15431289|ref|NM_000975.2 Homo   1E−300 sapiens ribosomal protein L11 (RPL11), mRNA 3655 RG:730938:10010:H04 MA159:H04 BC000580 gi|12653606|gb|BC000580.1BC000580 2.1E−254 Homo sapiens, clone IMAGE: 3162218, mRNA, partial cds 3656 RG:925984:10012:A10 MA161:A10 J03358 gi|339714|gb|J03358.1HUMTKFER 1.2E−246 Human tyrosine kinase (FER) mRNA, complete cds 3657 RG:668442:10010:B10 MA159:B10 X74764 gi|433337|emb|X74764.1HSRPTK 0 H. sapiens mRNA for receptor protein tyrosine kinase 3658 RG:1028911:10012:B10 MA161:B10 U88666 gi|1857943|gb|U88666.1HSU88666 Homo   1E−300 sapiens serine kinase SRPK2 mRNA, complete cds 3659 RG:684866:10010:C10 MA159:C10 X51521 gi|31282|emb|X51521.1HSEZRIN Human   1E−293 mRNA for ezrin 3660 RG:1283076:10012:F10 MA161:F10 BC007888 gi|14043894|gb|BC007888.1BC007888 0 Homo sapiens, eukaryotic translation initiation factor 2, subunit 2 (beta, 38 kD), clone MGC: 1417 3661 I:627654:17A01:G04 MA91:G04 AF081192 gi|3420798|gb|AF081192.1AF081192 0 Homo sapiens histone H2A.F/Z variant (H2AV) mRNA, complete cds 3662 I:1833801:17A01:D10 MA91:D10 BC009836 gi|14602636|gb|BC009836.1BC009836 1.9E−270 Homo sapiens, clone MGC: 15133 IMAGE: 4098463, mRNA, complete cds 3663 I:961473:17B01:H10 MA93:H10 0.20615 AK024678 gi|10437017|dbj|AK024678.1AK024678 2.7E−117 Homo sapiens cDNA: FLJ21025 fis, clone CAE06758 3664 I:2556708:09B01:B10 MA137:B10 BC018807 gi|17402954|gb|BC018807.1BC018807 1.6E−55 Homo sapiens, clone IMAGE: 4861487, mRNA 3665 RG:243565:10007:D10 MA156:D10 AF015254 gi|4090840|gb|AF015254.1AF015254 8.4E−186 Homo sapiens serine/threonine kinase (STK-1) mRNA, complete cds 3666 RG:266649:10007:G10 MA156:G10 AB034951 gi|11526572|dbj|A8034951.1AB034951   1E−300 Homo sapiens HSC54 mRNA for heat shock cognate protein 54, complete cds 3667 I:2013513:16B02:B04 MA90:B04 AF155913 gi|6435129|gb|AF155913.1AF155913 Mus 3.7E−51 musculus putative E1-E2 ATPase mRNA, complete cds 3668 I:2312442:16A02:B10 MA88:B10 0.38737 AK021945 gi|10433249|dbj|AK021945.1AK021945 1.9E−131 Homo sapiens cDNA FLJ11883 fis, clone HEMBA1007178 3669 I:2060626:16A02:D10 MA88:D10 AK055800 gi|16550622|dbj|AK055800.1AK055800 1.1E−191 Homo sapiens cDNA FLJ31238 fis, clone KIDNE2004864 3670 RG:1415858:10013:D04 MA162:D04 D85759 gi|1526445|dbj|D85759.1D85759 Homo 4.8E−271 sapiens mRNA for MNB protein kinase, complete cds 3671 RG:1517435:10013:F04 MA162:F04 X13546 gi|32328|emb|X13546.1HSHMG17G 6.7E−292 Human HMG-17 gene for non-histone chromosomal protein HMG-17 3672 RG:1914716:10015:H04 MA164:H04 X13697 gi|36414|emb|X13697.1HSSBLA Human   1E−300 mRNA for ribonucleoprotein SS-B/La 3673 RG:1354528:10013:A10 MA162:A10 AF197898 gi|6166494|gb|AF197898.1AF197898 6.7E−298 Homo sapiens nemo-like kinase mRNA, complete cds 3674 RG:1706414:10015:B10 MA164:B10 M36501 gi|177871|gb|M36501.1HUMA2MGL 0 Human alpha-2-macroglobulin mRNA, 3′ end 3675 I:1998510:17A02:C04 MA92:C04 BC004872 gi|13436100|gb|BC004872.1BC004872 1.4E−252 Homo sapiens, clone MGC: 11034 IMAGE: 3677618, mRNA, complete cds 3676 I:899118:17B02:G10 MA94:G10 AK055564 gi|16550323|dbj|AK055564.1AK0555.64   4E−159 Homo sapiens cDNA FLJ31002 fis, clone HLUNG2000004 3677 I:2680168:09B02:B04 MA138:B04 AL050071 gi|4884302|emb|AL050071.1HSM800396 0 Homo sapiens mRNA; cDNA DKFZp566B0846 (from clone DKFZp566B0846); partial cds 3678 I:1354558:09B02:E04 MA138:E04 AK054675 gi|16549267|dbj|AK054675.1AK054675   1E−156 Homo sapiens cDNA FLJ30113 fis, clone BNGH42000474 3679 I:1665871:09B02:F10 MA138:F10 AF288394 gi|12620197|gb|AF288394.1AF288394 0 Homo sapiens Clorf19 mRNA, partial cds 3680 I:1922084:18B01:C05 MA97:C05 AK000057 gi|7019894|dbj|AK000057.1AK000057 1.3E−246 Homo sapiens cDNA FLJ20050 fis, clone COL00688 3681 I:2307946:18A01:B11 MA95:B11 BC016150 gi|16740553|gb|BC016150.1BC016150 8.9E−226 Homo sapiens, Similar to CAP-binding protein complex interacting protein 2, clone IMAGE: 3637027, 3682 I:1923572:18B01:C11 MA97:C11 AL049959 gi|4884211|emb|AL049959.1HSM800304 2.3E−154 Homo sapiens mRNA; cDNA DKFZp564K1023 (from clone DKFZp564K1023) 3683 RG:171993:10006:F05 MA155:F05 0.31835 AK057735 gi|16553657|dbj|AK057735.1AK057735 3.9E−142 Homo sapiens cDNA FLJ25006 fis, clone CBL00989 3684 RG:129317:10006:B11 MA155:B11 AF103796 gi|4185795|gb|AF103796.1AF103796   1E−300 Homo sapiens placenta-specific ATP- binding cassette transporter (ABCP) mRNA, complete cds 3685 RG:153244:10006:D11 MA155:D11 L06139 gi|292823|gb|L06139.1HUMTEKRPTK 1.1E−299 Homo sapiens receptor protein-tyrosine kinase (TEK) mRNA, complete cds 3686 RG:196236:10006:H11 MA155:H11 AF359246 gi|13991617|gb|AF359246.1AF359246   5E−249 Homo sapiens fibroblast growth factor receptor 4 variant mRNA, complete cds 3687 I:557538:16A01:C11 MA87:C11 BC013142 gi|15341912|gb|BC013142.1BC013142 1.1E−240 Homo sapiens, interleukin 1, alpha, clone MGC: 9225 IMAGE: 3875617, mRNA, complete cds 3688 I:782235:16A01:F11 MA87:F11 K01228 gi|180391|gb|K01228.1HUMCG1PA1   9E−251 Human proalpha 1 (I) chain of type I procollagen mRNA (partial) 3689 RG:1257341:10012:F05 MA161:F05 BC007952 gi|14044057|gb|BC007952.1BC007952   1E−300 Homo sapiens, pyruvate kinase, muscle, clone MGC: 14360 IMAGE: 4299213, mRNA, complete cds 3690 RG:727387:10010:G05 MA159:G05 BC001413 gi|13937593|gb|BC001413.1BC001413 0 Homo sapiens, clone IMAGE: 3140866, mRNA 3691 RG:1145235:10012:D11 MA161:D11 BC007540 gi|14043108|gb|BC007540.1BC007540 3.4E−71 Homo sapiens, clone IMAGE: 3609337, mRNA, partial cds 3692 RG:725145:10010:F11 MA159:F11 AJ000512 gi|2463200|emb|AJ000512.1HSSGK 8.4E−264 Homo sapiens sgk gene 3693 RG:740079:10010:H11 MA159:H11 M14505 gi|456426|gb|M14505.1HUMCDPK 0 Human (clone PSK-J3) cyclin-dependent protein kinase mRNA, complete cds., 3694 I:1873176:09B01:E05 MA137:E05 BC001909 gi|12804912|gb|BC001909.1BC001909 0 Homo sapiens, clone IMAGE: 3537447, mRNA, partial cds 3695 I:2081974:09B01:D11 MA137:D11 AK057078 gi|16552660|dbj|AK057078.1AK057078 0 Homo sapiens cDNA FLJ32516 fis, clone SMINT1000103, highly similar to Homo sapiens ankyrin repea 3696 I:2107723:18A02:G05 MA96:G05 AK000193 gi|7020116|dbj|AK000193.1AK000193 1.2E−265 Homo sapiens cDNA FLJ20186 fis, clone COLF0428 3697 RG:207777:10007:B11 MA156:B11 X04714 gi|28779|emb|X04714.1HSAPOB10   1E−300 Human mRNA for apolipoprotein B-100 (apoB-100) 3698 RG:221172:10007:C11 MA156:C11 M14333 gi|181171|gb|M14333.1HUMCSYNA 2.2E−97 Homo sapiens c-syn protooncogene mRNA, complete cds 3699 I:1968436:16B02:C05 MA90:C05 0.33281 3700 I:2060973:16A02:G11 MA88:G11 AB035384 gi|7619897|dbj|AB035384.1AB035384 2.6E−291 Homo sapiens mRNA for SRp25 nuclear protein, complete cds 3701 RG:1369494:10013:B05 MA162:B05 AF008552 gi|2979629|gb|AF008552.1AF008552   1E−300 Homo sapiens aurora-related kinase 2 (ARK2) mRNA, complete cds 3702 RG:1752177:10015:E05 MA164:E05 3703 RG:1519327:10013:F05 MA162:F05 X66364 gi|36620|emb|X66364.1HSSTHPKE 0 H. sapiens mRNA PSSALRE for serine/threonine protein kinase 3704 RG:1694569:10015:A11 MA164:A11 X06323 gi|34753|emb|X06323.1HSMRL3R Human 0 MRL3 mRNA for ribosomal protein L3 homologue (MRL3 = mammalian ribosome L3) 3705 RG:1839794:10015:E11 MA164:E11 U28387 gi|881950|gb|U28387.1HSU28387 Human 5.2E−175 hexokinase II pseudogene, complete cds 3706 I:514124:17A02:D05 MA92:D05 AJ420434 gi|17066298|emb|AJ420434.1HSA420434 6.5E−114 Homo sapiens mRNA full length insert cDNA clone EUROIMAGE 1499812 3707 I:997782:17A02:G05 MA92:G05 AB018346 gi|3882326|dbj|AB018346.1AB018346 2.8E−185 Homo sapiens mRNA for KIAA0803 protein, partial cds 3708 I:1709364:09B02:F11 MA138:F11 NM_018440 gi|16753228|ref|NM_018440.2 Homo 6.4E−180 sapiens phosphoprotein associated with glycosphingolipid-enriched microdomains (PAG), mRNA 3709 I:2004896:18A01:C06 MA95:C06 AK023512 gi|10435467|dbj|AK023512.1AK023512   2E−117 Homo sapiens cDNA FLJ13450 fis, clone PLACE1003027, highly similar to Homo sapiens mRNA for KIAA 3710 RG:172982:10006:F06 MA155:F06 D83492 gi|2281007|dbj|D83492.1D83492 Homo 0 sapiens mRNA for Eph-family protein, complete cds 3711 RG:180978:10006:G06 MA155:G06 D83492 gi|2281007|dbj|D83492.1D83492 Homo 0 sapiens mRNA for Eph-family protein, complete cds 3712 RG:129528:10006:B12 MA155:B12 U00238 gi|404860|gb|U00238.1U00238 Homo 1.6E−286 sapiens glutamine PRPP amidotransferase (GPAT) mRNA, complete cds 3713 RG:186511:10006:G12 MA155:G12 AK000250 gi|7020204|dbj|AK000250.1AK000250 3.4E−204 Homo sapiens cDNA FLJ20243 fis, clone COLF6418, highly similar to NUCL_HUMAN NUCLEOLIN 3714 I:2005910:16B01:B06 MA89:B06 AJ340058 gi|15884476|emb|A1340058.1HSA340058 2.8E−110 Homo sapiens genomic sequence surrounding NotI site, clone NR5-ID23C 3715 I:620871:16A01:D06 MA87:D06 BC007422 gi|13938544|gb|BC007422.1BC007422 3.5E−250 Homo sapiens, acid phosphatase 1, soluble, clone MGC: 3499 IMAGE: 3027769, mRNA, complete cds 3716 I:1920819:16A01:A12 MA87:A12 BC015123 gi|15929378|gb|BC015123.1BC015123 8.2E−276 Homo sapiens, Similar to retinoblastoma- binding protein 4, clone IMAGE: 3686783, mRNA, partial cds 3717 I:990375:16A01:E12 MA87:E12 M10050 gi|182355|gb|M10050.1HUMFABPL 1.8E−267 Human liver fatty acid binding protein (FABP) mRNA, complete cds 3718 I:690313:16A01:G12 MA87:G12 BC017201 gi|16877960|gb|BC017201.1BC017201 3.8E−200 Homo sapiens, insulin-like growth factor binding protein 7, clone MGC: 3699 IMAGE: 3632247, mRNA, c 3719 RG:878195:10012:A06 MA161:A06 M83653 gi|179635|gb|M83653.1HUMC1PHTYR 0 Homo sapiens cytoplasmic phosphotyrosyl protein phosphatase (clone type 1) complete cds 3720 RG:687128:10010:D06 MA159:D06 S75546 gi|914097|gb|S75546.1S75546 protein 1.7E−38 kinase PRK1 [human, fetal brain, mRNA, 3001 nt] 3721 I:884855:17B01:D06 MA93:D06 AK055393 gi|16550110|dbj|AK055393.1AK055393   4E−228 Homo sapiens cDNA FLJ30831 fis, clone FEBRA2001989 3722 I:1218621:17B01:F06 MA93:F06 3723 I:620371:17A01:H06 MAA91:H06 BC016472 gi|16741273|gb|BC016472.1BC016472   1E−203 Homo sapiens, clone MGC: 17244 IMAGE: 4178911, mRNA, complete cds 3724 I:1681610:09B01:D06 MA137:D06 AK055827 gi|16550653|dbj|AK055827.1AK055827 1.3E−124 Homo sapiens cDNA FLJ31265 fis, clone KIDNE2006030, moderately similar to Gallus gallus syndesmo 3725 RG:265206:10007:G06 MA156:G06 U25975 gi|984304|gb|U25975.1HSU25975 Human   1E−231 serine kinase (hPAK65) mRNA, partial cds 3726 RG:268073:10007:H06 MA156:H06 AF226044 gi|9295326|gb|AF226044.1AF226044 9.8E−118 Homo sapiens HSNFRK (HSNFRK) mRNA, complete cds 3727 I:2117221:16A02:F06 MA88:F06 0.22151 AF130089 gi|11493482|gb|AF130089.1AF130089 9.5E−152 Homo sapiens clone FLB9440 PRO2550 mRNA, complete cds 3728 I:1760693:16B02:G06 MA90:G06 3729 I:776793:16B02:B12 MA90:B12 AF086524 gi|3483869|gb|AF086524.1HUMZE04F10 1.5E−283 Homo sapiens full length insert cDNA clone ZE04F10 3730 RG:1405692:10013:C06 MA162:C06 X60489 gi|31099|emb|X60489.1HSEF1B Human 0 mRNA for elongation factor-1-beta 3731 RG:1707747:10015:B12 MA164:B12 M29536 gi|182066|gb|M29536.1HUMELF2 Human 0 translational initiation factor 2 beta subunit (elF-2-beta) mRNA, complete cds 3732 RG:1722789:l0015:C12 MA164:C12 AF183421 gi|9963780|gb|AF183421.1AF183421 0 Homo sapiens small GIP-binding protein rab22b mRNA, complete cds 3733 I:2112348:17B02:E06 MA94:E06 AK026529 gi|10439407|dbj|AK026529.1AK026529 1.7E−196 Homo sapiens cDNA: FLJ22876 fis, clone KAT02954, highly similar to AF056183 Homo sapiens WS beta 3734 I:630458:17A02:F06 MA92:F06 AK025537 gi|10438082|dbj|AK025537.1AK025537 7.2E−211 Homo sapiens cDNA: FLJ21884 fis, clone HEP02863 3735 I:901577:17A02:H06 MA92:H06 AK000771 gi|7021067|dbj|AK000771.1AK00077l 2.3E−195 Homo sapiens cDNA FLJ20764 fis, clone COL08503 3736 I:2298081:17B02:E12 MA94:E12 AL080169 gi|5262637|emb|AL080169.1HSM800688 0 Homo sapiens mRNA; cDNA DKFZp434C171 (from clone DKFZp434C171); partial cds 3737 I:2718565:09B02:H12 MA138:H12 AF207600 gi|9998951|gb|AF207600.2AF207600 3.2E−253 Homo sapiens ethanolamine kinase (EMI1) mRNA, complete cds 3738 M00056237C:E03 MA181:A01 0.8773 U27317 gi|9989705|gb|U27317.2HSHSD11K1 7.9E−23 Homo sapiens 11 beta-hydroxysteroid dehydrogenase 2 (HSD11B2) gene, complete cds 3739 M00055261C:F04 MA197:E01 NM_033643 gi|16117795|ref|NM_033643.1 Homo 8.3E−223 sapiens ribosomal protein L36 (RPL36), transcript variant 1, mRNA 3740 M00055353D:A04 MA197:D07 BC006794 gi|13905021|gb|BC006794.1BC006794 1.1E−156 Homo sapiens, Similar to interferon induced transmembrane protein 3 (1-8U), clone MGC: 5225 IMAGE: 3741 M00055357B:B10 MA197:H07 BC006794 gi|13905021|gb|BC006794.1BC006794   3E−275 Homo sapiens, Similar to interferon induced transmembrane protein 3 (1-8U), clone MGC: 5225 IMAGE: 3742 M00056386D:H12 MA173:C01 BC007700 gi|14712760|gb|BC007700.1BC007700 6.1E−180 Homo sapiens, clone IMAGE: 3954272, mRNA 3743 M00056394B:B04 MA173:D01 BC006791 gi|13905015|gb|BC006791.1BC006791   1E−175 Homo sapiens, ribosomal protein L10a, clone MGC: 5203 IMAGE: 2901249, mRNA, complete cds 3744 M00056395A:B04 MA173:E01 BC016835 gi|16877126|gb|BC016835.1BC016835 4.2E−55 Homo sapiens, Similar to synaptophysin- like protein, clone MGC: 10011 IMAGE: 3883697, mRNA, complet 3745 M00056396B:G05 MA173:F01 AK026171 gi|10438934|dbj|AK026171.1AK026171 2.9E−94 Homo sapiens cDNA: FLJ22518 fis, clone HRC12216, highly similar to AF151069 Homo sapiens HSPC235 3746 M00056137A:A05 MA180:G01 3747 M00056401C:C03 MA173:H01 L20688 gi|404044|gb|L20688.1HUMLYGDI 6.4E−267 Human GDP-dissociation inhibitor protein (Ly-GDI) mRNA, complete cds 3748 M00056484A:F06 MA173:E07 NM_003145 gi|6552341|ref|NM_003145.2 Homo 1.3E−252 sapiens signal sequence receptor, beta (translocon-associated protein beta) (SSR2), mRNA 3749 M00056193B:C11 MA180:F07 AF119905 gi|7770246|gb|AF119905.1AF119905 4.6E−193 Homo sapiens PRO2853 mRNA, complete cds 3750 M00056484B:B07 MA173:G07 AF203815 gi|6979641|gb|AF203815.1AF203815 6.6E−214 Homo sapiens alpha gene sequence 3751 M00056193B:D06 MA180:G07 AF004162 gi|3046385|gb|AF004162.1AF004162 8.3E−201 Homo sapiens nickel-specific induction protein (Cap43) mRNA, complete cds 3752 M00056194B:G06 MA180:H07 BC016834 gi|16877123|gb|BC016834.1BC016834 2.5E−294 Homo sapiens, clone IMAGE: 3883264, mRNA, partial cds 3753 M00054633D:B07 MA187:A01 BC018210 gi|17390469|gb|BC018210.1BC018210 7.9E−279 Homo sapiens, tubulin-specific chaperone a, clone MGC: 9129 IMAGE: 3861138, mRNA, complete cds 3754 M00054633D:E06 MA187:B01 X52003 gi|311379|emb|X52003.1HSPS2MKN   3E−275 H. sapiens pS2 protein gene 3755 M000548458A:C03 MA189:H01 NM_001010 gi|17158043|ref|NM_001010.2 Homo 3.6E−287 sapiens ribosomal protein S6 (RPS6), mRNA 3756 M00054882C:C06 MA189:A07 BC000915 gi|14705283|gb|BC000915.2BC000915 5.3E−283 Homo sapiens, PDZ and LIM domain 1 (elfin), clone MGC: 5344 IMAGE: 2985229. mRNA, complete cds 3757 M00054678D:A03 MA187:B07 BC015564 gi|15990405|gb|BC015564.1BC015564 7.8E−279 Homo sapiens, cold shock domain protein A, clone MGC: 12695 IMAGE: 4137643, mRNA, complete cds 3758 M00054679B:B03 MA187:D07 BC015642 gi|15990506|gb|BC015642.1BC015642 4.8E−277 Homo sapiens, Similar to serine (or cysteine) protemase inhibitor, clade A (alpha-1 antiproteina 3759 M00054680B:D06 MA187:G07 BC009623 gi|16307089|gb|BC009623.1BC009623 8.4E−279 Homo sapiens, Similar to nucleophosmin (nucleolar phosphoprotein B23, numatrin), clone MGC: 17308 3760 M00054680C:A06 MA187:H07 U28387 gi|881950|gb|U28387.1HSU28387 Human   9E−83 hexokinase II pseudogene, complete cds 3761 M00057176B:F11 MA193:B01 BC000419 gi|12653300|gb|BC000419.1BC000419 1.1E−296 Homo sapiens, catechol-O- methyltransferase, clone MGC: 8663 IMAGE: 2964400, mRNA, complete cds 3762 M00057181A:D01 MA193:C01 AY008283 gi|15192138|gb|AY008283.1 Homo 4.9E−196 sapiens porimin mRNA, complete cds 3763 M00057219D:B04 MA193:D07 NM_001015 gi|14277698|ref|NM_001015.2 Homo 3.4E−175 sapiens ribosomal protein S11 (RPS11), mRNA 3764 M00042341A:D12 MA167:A01 NM_002153 gi|4504502|ref|NM_002153.1 Homo 8.3E−123 sapiens hydroxysteroid (17-beta) dehydrogenase 2 (HSD17B2), mRNA 3765 M00042433B:G09 MA171:B01 AJ295637 gi|9581767|emb|AJ295637.1HSA295637 1.2E−221 Homo sapiens mRNA for URIM protein 3766 M00042435A:F08 MA171:D01 BC014048 gi|15559357|gb|BC014048.1BC014048 4.6E−122 Homo sapiens, clone IMAGE: 3348134, mRNA, partial cds 3767 M00042437B:G03 MA171:E01 X59315 gi|33247|emb|X59315.1HSIGKL012 1.5E−119 H. sapiens gene for Ig kappa light chain variable region “012” 3768 M00042525D:E07 MA167:F01 BC005982 gi|13543665|gb|BC005982.1BC005982 1.4E−105 Homo sapiens, peptidylprolyl isomerase A (cyclophilin A), clone MGC: 14681 IMAGE: 4109260, mRNA, co 3769 M00042438B:D01 MA171:F01 NM_004063 gi|16507959|ref|NM_004063.2 Homo 6.1E−264 sapiens cadherin 17, LI cadherin (liver- intestine) (CDH17), mRNA 3770 M00042529C:G07 MA167:G01 L02785 gi|291963|gb|L02785.1HUMDRA Homo 5.8E−261 sapiens colon mucosa-associated (DRA) mRNA, complete cds 3771 M00042529D:B12 MA167:H01 0.07368 BC007011 gi|13937818|gb|BC007011.1BC007011 2.1E−145 Homo sapiens, clone MGC: 12335 IMAGE: 3686576, mRNA, complete cds 3772 M00042700A:E05 MA167:A07 U07550 gi|469170|gb|U07550.1HSU075501Human 4.1E−212 chaperonin 10 mRNA, complete cds 3773 M00042777D:G05 MA171:B07 AY007243 gi|12621025|gb|AY007243.1 Homo 6.1E−264 sapiens regenerating gene type IV mRNA, complete cds 3774 M00042781C:F03 MA171:D07 BC016753 gi|16876954|gb|BC016753.1BC016753 3.7E−259 Homo sapiens, clone MGC: 1138 IMAGE: 2987963, mRNA, complete cds 3775 M00042783C:F10 MA171:E07 0.80366 3776 M00042702D:B02 MA167:F07 AJ010446 gi|3954892|emb|AJ010446.1HSA010446 2.8E−154 Homo sapiens mRNA for immunoglobulin kappa light chain, anti-RhD, therad 24 3777 M00042785B:F11 MA171:H07 AF254415 gi|13897565|gb|AF254415.1AF254415 3.9E−209 Homo sapiens gastrointestinal secretory protein GISP mRNA, complete cds 3778 M00056566C:C03 MA174:A07 NM_031901 gi|16950594|ref|NM_031901.2 Homo 1.4E−255 sapiens mitochondrial ribosomal protein S21 (MRPS21), transcript variant 1, nuclear gene encoding 3779 M00056567B:A09 MA174:C07 BC000396 gi|12653254|gb|BC000396.1BC000396   1E−293 Homo sapiens, ubiquitin-conjugating enzyme E2N (homologous to yeast UBC13), clone MGC: 8489 IMAGE: 3780 M00056569B:D09 MA174:G07 U61267 gi|1418285|gb|U61267.1HSU61267 Homo 4.4E−243 sapiens putative splice factor transformer2- beta mRNA, complete cds 3781 M00056571D:E05 MA174:H07 BC017696 gi|17389285|gb|BC017696.1BC017696 6.6E−239 Homo sapiens, Similar to RIKEN cDNA 2410075D05 gene, clone MGC: 21057 IMAGE: 4393374, mRNA, complet 3782 RG:376801:10009:C01 MA158:C01 AB017642 gi|4519628|dbj|AB017642.1AB017642 8.9E−282 Homo sapiens mRNA for oxidative-stress responsive 1, complete cds 3783 RG:365436:10009:B07 MA158:B07 AK022055 gi|10433374|dbj|AK022055.1AK022055 1.1E−290 Homo sapiens cDNA FLJ11993 fis, clone HEMBB1001429, highly similar to Homo sapiens leucine amino 3784 RG:416839:10009:D07 MA158:D07 AK026432 gi|10439295|dbj|AK026432.1AK026432 0 Homo sapiens cDNA: FLJ22779 fis, clone KAIA1741 3785 RG:784224:10011:E07 MA160:E07 L03840 gi|182570|gb|L03840.1HUMFGFR4X 7.3E−258 Human fibroblast growth factor receptor 4 (FGFR4) mRNA, complete cds 3786 RG:796852:10011:G07 MA160:G07 AF087909 gi|10121889|gb|AF087909.1AF087909 4.4E−271 Homo sapiens NIMA-related kinase 6 (NEK6) mRNA, complete cds 3787 M00043412A:F04 MA184:E01 NM_000993 gi|15812219|ref|NM_000993.2 Homo 8.3E−158 sapiens ribosomal protein L31 (RPL31), mRNA 3788 M00057273B:H10 MA182:H01 AB042820 gi|11041627|dbj|AB042820.1AB042820 5.6E−41 Homo sapiens RPL6 gene for ribosomal protein L6, complete cds 3789 M00054506C:B10 MA184:B07 NM_001012 gi|4506742|ref|NM_001012.1 Homo 2.6E−185 sapiens ribosomal protein S8 (RPS8), mRNA 3790 M00054507D:G03 MA184:F07 U19765 gi|790570|gb|U19765.1HSU19765 Human 1.5E−221 nucleic acid binding protein gene, complete cds 3791 M00054935B:B03 MA198:E01 0.06563 NM_001644 gi|5921993|ref|NM_001644.2 Homo 1.2E−128 sapiens apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1), transcript variant 3792 M00054935D:C11 MA198:H01 NM_002026 gi|16933541|ref|NM_002026.1 Homo 1.1E−190 sapiens fibronectin 1 (FN1), transcript variant 1, mRNA 3793 M00054976A:E09 MA198:D07 BC017189 gi|16877928|gb|BC017189.1BC017189 2.7E−188 Homo sapiens, myo-inositol 1-phosphate synthase A1, clone MGC: 726 IMAGE: 3140452, mRNA, complete c 3794 M00055788B:F08 MA170:C07 V00662 gi|13003|emb|V00662.1MIHSXX 1.3E−165 H. sapiens mitochondrial genome 3795 M00055791A:E10 MA170:G07 X01117 gi|57149|emb|X01117.1RNRRNA06 Rat   7E−92 18S rRNA sequence 3796 M00055224C:H11 MA196:E07 BC008952 gi|14286301|gb|BC008952.1BC008952   5E−171 Homo sapiens, lactate dehydrogenase B, clone MGC: 3600 IMAGE: 3028947, mRNA, complete cds 3797 M00055932A:C02 MA179:B01 BC019362 gi|17939458|gb|BC019362.1BC019362 2.1E−226 Homo sapiens, guanine nucleotide binding protein (G protein), beta polypeptide 2-like 1, clone MG 3798 M00056908A:F12 MA177:C01 0.86486 3799 M00055935D:B06 MA179:D01 D17041 gi|598766|dbj|D17041.1HUMD3F06M5 3.3E−182 Human HepG2 partial cDNA, clone hmd3f06m5 3800 M00056908D:D08 MA177:E01 AK026649 gi|10439547|dbj|AK026649.1AK026649 2.3E−154 Homo sapiens cDNA: FLJ22996 fis, clone KAT11938 3801 M00055942B:F08 MA179:F01 X98311 gi|1524059|emb|X98311.1HSCGM2ANT 5.9E−196 H. sapiens mRNA for carcinoembryonic antigen family member 2, CGM2 3802 M00056910A:B07 MA177:G01 BC009599 gi|16307042|gb|BC009599.1BC009599 8.3E−254 Homo sapiens, clone MGC: 14690 IMAGE: 4134557, mRNA, complete cds 3803 M00056952B:C08 MA177:H07 Z85181 gi|1834892|emb|Z85181.1HSZ85181   8E−186 H. sapiens Ig lambda light chain variable region gene (6-09OIIA61) rearranged; Ig- Light-Lambda; VLam 3804 M00054728C:E03 MA188:A01 M34664 gi|184411|gb|M34664.1HUMHSP60A 1.3E−283 Human chaperonin (HSP60) mRNA, complete cds 3805 M00054728D:E06 MA188:B01 X16064 gi|37495|emb|X16064.1HSTUMP Human   1E−300 mRNA for translationally controlled tumor protein 3806 M00054731C:H01 MA188:H01 X73502 gi|406853|emb|X73502.1HSENCY20 H. Sapiens 1.9E−267 mRNA for cytokeratin 20 3807 M00054778B:A12 MA188:D07 AJ276249 gi|7362984|emb|AJ276249.1HSA276249   2E−91 Homo sapiens partial mRNA, clone cl- 10e16 3808 M00054778C:D08 MA188:F07 NM_002137 gi|14043073|ref|NM_002137.2 Homo 1.8E−34 sapiens heterogeneous nuclear ribonucleoprotein A2/B1 (HNRPA2B1), transcript variant A2, mRNA 3809 M00054780A:G06 MA188:H07 BC000035 gi|12652584|gb|BC000035.1BC000035 3.6E−287 Homo sapiens, CGI-89 protein, clone MGC: 845 IMAGE: 3506601, mRNA, complete cds 3810 M00042899D:D02 MA168:A01 Y00339 gi|29586|emb|Y0039.1HSCA2 Human 1.5E−233 mRNA for carbonic anhydrase II (EC 4.2.1.1) 3811 M00042831B:G10 MA172:C01 AK024740 gi|10437104|dbj|AK024740.1AK024740 6.2E−264 Homo sapiens cDNA: FLJ21087 fis, clone CAS03323 3812 M00042833A:G07 MA172:D01 AF047470 gi|2906145|gb|AF047470.1AF047470   3E−166 Homo sapiens malate dehydrogenase precursor (MDH) mRNA, nuclear gene encoding mitochondrial protei 3813 M00042906D:F05 MA168:E01 L31792 gi|471076|gb|L31792.1HUMCGM2A 1.1E−200 Homo sapiens carcinoembryonic antigen (CGM2) mRNA, complete cds 3814 M00042910C:A02 MA168:G01 AF113700 gi|6855634|gb|AF113700.1AF113700 7.6E−245 Homo sapiens clone FLB9737 3815 M00042838C:D06 MA172:H01 AK026558 gi|10439440|dbj|AK026558.1AK026558 1.7E−214 Homo sapiens cDNA: FLJ22905 fis, clone KAT05654, highly similar to HUMRPL18A Homo sapiens riboso 3816 M00042867B:F03 MA172:A07 0.30983 D87666 gi|1620016|dbj|D87666.1D87666 Human 1.3E−101 heart mRNA for heat shock protein 90, partial cds 3817 M00055439B:G05 MA168:B07 AY029066 gi|14017398|gb|AY029066.1 Homo 9.6E−263 sapiens Humanin (HN1) mRNA, complete cds 3818 M00055442D:E12 MA168:F07 BC005354 gi|13529169|gb|BC005354.1BC005354 6.6E−239 Homo sapiens, ribosomal protein, large P2, clone MGC: 12453 IMAGE: 4052568, mRNA, complete cds 3819 M00056711D:A02 MA175:B01 Z11566 gi|1066270|emb|Z11566.1HSPR22MR 6.7E−133 H. sapiens mRNA for Pr22 protein 3820 M00056771C:A12 MA175:A07 X02152 gi|34312|emb|X02152.1HSLDHAR   6E−130 Human mRNA for lactate dehydrogenase- A (LDH-A, EC 1.1.1.27) 3821 M00056772D:G07 MA175:C07 NM_001016 gi|14277699|ref|NM_001016.2 Homo 1.2E−218 sapiens ribosomal protein S12 (RPS12), mRNA 3822 M00056782D:E04 MA175:F07 AF346968 gi|13272626|gb|AF346968.1AF346968 3.6E−172 Homo sapiens mitochondrion, complete genome 3823 M00056785D:G01 MA175:G07 NM_001019 gi|14165468|ref|NM_001019.2 Homo 1.5E−230 sapiens ribosomal protein S15a (RPS15A), mRNA 3824 M00056788C:A01 MA175:H07 AY029066 gi|14017398|gb|AY029066.1 Homo 3.5E−287 sapiens Humanin (HN1) mRNA, complete cds 3825 RG:1663880:10014:F07 MA163:F07 BC019315 gi|17939511|gb|BC019315.1BC019315   1E−300 Homo sapiens, N-acetylneuraminic acid phosphate synthase; sialic acid synthase, clone MGC: 4339 IM 3826 M00043310B:D08 MA183:C01 NM_000969 gi|14591908|ref|NM_000969.2 Homo 1.5E−261 sapiens ribosomal protein L5 (RPL5), mRNA 3827 M00054538C:G03 MA185:C01 BC000734 gi|12653884|gb|BC000734.1BC000734   4E−234 Homo sapiens, eukaryotic translation initiation factor 3, subunit 6 (48 kD), clone MGC: 2060 IMAGE: 3828 M00043315C:G05 MA183:H01 AK023362 gi|10435266|dbj|AK023362.1AK023362 2.7E−241 Homo sapiens cDNA FLJ13300 fis, clone OVARC1001342, highly similar to 40S RIBOSOMAL PROTEIN S8 3829 M00055397B:E08 MA199:B01 X06747 gi|36101|emb|X06747.1HSRNPA1 Human 9.7E−132 hnRNP core protein A1 3830 M00056624B:H11 MA186:C01 X56597 gi|31394|emb|X56597.1HSFIB Human 7.7E−192 humFib mRNA for fibrillarin 3831 M00055423C:C03 MA199:E07 L01124 gi|307390|gb|L01124.1HUMRPS13A 9.1E−154 Human ribosomal protein S13 (RPS13) mRNA, complete cds 3832 M00056668D:C06 MA186:F07 BC013231 gi|15301504|gb|BC013231.1BC013231 9.8E−263 Homo sapiens, clone IMAGE: 3462987, mRNA 3833 M00056669B:A10 MA186:G07 NM_001025 gi|14790142|ref|NM_001025.2 Homo 3.7E−290 sapiens ribosomal protein S23 (RPS23), mRNA 3834 M00055424A:D01 MA199:G07 BC002362 gi|12803116|gb|BC002362.1BC002362 6.4E−183 Homo sapiens, lactate dehydrogenase B, clone MGC: 8627 IMAGE: 2961445, mRNA, complete cds 3835 M00056669B:E07 MA186:H07 NM_002295 gi|9845501|ref|NM_002295.2 Homo 9.1E−232 sapiens laminin receptor 1 (67 kD, ribosomal protein SA) (LAMR1), mRNA 3836 M00055424D:F01 MA199:H07 NM_001012 gi|4506742|ref|NM_001012.1 Homo 4.4E−190 sapiens ribosomal protein S8 (RPS8), mRNA 3837 M00056243A:H07 MA181:C02 0.86405 3838 M00056243C:G10 MA181:D02 0.46512 3839 M00055528D:H03 MA169:F02 0.6783 3840 M00055607B:A11 MA169:B08 AF161415 gi|6841243|gb|AF161415.1AF161415 3.5E−253 Homo sapiens HSPC297 mRNA, partial cds 3841 M00055363C:E02 MA197:A08 0.62737 3842 M00055373D:H02 MA197:F08 BC013016 gi|15278200|gb|BC013016.1BC013016 3.3E−125 Homo sapiens, Similar to ribosomal protein L19, clone MGC: 4526 IMAGE: 3010178, mRNA, complete cds 3843 M00055374D:E01 MA197:H08 NM_000979 gi|15431298|ref|NM_000979.2 Homo 1.5E−261 sapiens ribosomal protein L18 (RPL18), mRNA 3844 M00056401D:D09 MA173:A02 BC008492 gi|14250147|gb|BC008492.1BC008492 1.6E−105 Homo sapiens, ribosomal protein L3, clone MGC: 14821 IMAGE: 4251511, mRNA, complete cds 3845 M00056139D:A10 MA180:B02 X16356 gi|37203|emb|X16356.1HSTM3CEA 3.9E−237 Human mRNA for transmembrane carcinoembryonic antigen BGPC (part.) (formerly TM3-CEA) 3846 M00056140A:E11 MA180:D02 U96628 gi|2343084|gb|U96628.1HSU96628 Homo 2.4E−182 sapiens nuclear antigen H731-like protein mRNA, complete cds 3847 M00056142D:A08 MA180:E02 BC015958 gi|16358989|gb|BC015958.1BC015958 4.2E−268 Homo sapiens, clone MGC: 15290 IMAGE: 3940309, mRNA, complete cds 3848 M00056412D:A09 MA173:F02 0.85039 3849 M00056142D:H11 MA180:F02 AK025078 gi|10437520|dbj|AK025078.1AK025078 3.8E−120 Homo sapiens cDNA: FLJ21425 fis, clone COL04162 3850 M00056414C:F03 MA173:G02 M29548 gi|181966|gb|M29548.1HUMEF1AB 1.7E−114 Human elongation factor 1-alpha (EF1A) mRNA, partial cds 3851 M00056196A:H09 MA180:B08 D84239 gi|1944351|dbj|D84239.1D84239 Homo   2E−251 sapiens mRNA for IgG Fc binding protein, complete cds 3852 M00056200A:E11 MA180:D08 U14528 gi|549987|gb|U14528.1HSU14528 Human 4.3E−299 sulfate transporter (DTD) mRNA, complete cds 3853 M00056488C:G01 MA173:E08 L08048 gi|184250|gb|L08048.1HUMHMG1C 3.3E−281 Human non-histone chromosomal protein (HMG-1) retropseudogene 3854 M00056200B:B01 MA180:E08 D84239 gi|1944351|dbj|D84239.1D84239 Homo 1.5E−233 sapiens mRNA for IgG Fc binding protein, complete cds 3855 M00056203B:G08 MA180:F08 0.89391 3856 M00056493A:F09 MA173:H08 X14831 gi|37199|emb|X14831.1HSTM2CEA 4.2E−115 Human mRNA for transmembrane carcinoembryonic antigen BGPb (formerly TM2-CEA) 3857 M00054640D:D12 MA187:B02 0.89884 3858 M00054643B:F04 MA187:D02 0.66848 3859 M00054643C:D08 MA187:E02 BC000491 gi|12653440|gb|BC000491.1BC000491 1.6E−236 Homo sapiens, proliferating cell nuclear antigen, clone MGC: 8367 IMAGE: 2820036, mRNA, complete cd 3860 M00054854D:B06 MA189:F02 M16660 gi|184420|gb|M16660.1HUMHSP90 2.4E−263 Human 90-kDa heat-shock protein gene, cDNA, complete cds 3861 M00054644B:F02 MA187:G02 BC017414 gi|16924273|gb|BC017414.1BC017414 1.2E−246 Homo sapiens, Similar to signal recognition particle 9 kD, clone IMAGE: 4655251, mRNA, partial cds 3862 M00054857A:E08 MA189:G02 BC016753 gi|16876954|gb|BC016753.1BC016753 8.6E−229 Homo sapiens, clone MGC: 1138 IMAGE: 2987963, mRNA, complete cds 3863 M00054681D:G03 MA187:B08 BC019360 gi|17939583|gb|BC019360.1BC019360   1E−300 Homo sapiens, clone IMAGE: 4025624, mRNA 3864 M00054682D:F11 MA187:D08 0.13542 AF116637 gi|7959775|gb|AF116637.1AF116637 3.2E−210 Homo sapiens PRO1489 mRNA, complete cds 3865 M00054684B:C07 MA187:F08 BC001781 gi|12804704|gb|BC001781.1BC001781 8.6E−176 Homo sapiens, ribosomal protein L44, clone MGC: 2064 IMAGE: 3353669, mRNA, complete cds 3866 M00057191B:E11 MA193:D02 AK026528 gi|10439405|dbj|AK026528.1AK026528 4.6E−274 Homo sapiens cDNA: FLJ22875 fis, clone KAT02879 3867 M00057194B:G12 MA193:G02 AF228422 gi|12656020|gb|AF228422.1AF228422 1.9E−117 Homo sapiens normal mucosa of esophagus specific 1 (NMES1) mRNA, complete cds 3868 M00057222D:G09 MA193:B08 D49400 gi|1395161|dbj|D49400.1HUMVATPASE 3.9E−262 Homo sapiens mRNA for vacuolar ATPase, complete cds 3869 M00042531B:H03 MA167:A02 M15042 gi|180198|gb|M15042.1HUMCEA Human 6.3E−211 carcinoembryonic antigen mRNA 3870 M00042440C:G04 MA171:A02 0.89441 3871 M00042533C:D02 MA167:C02 X56999 gi|37568|emb|X56999.1HSUBA52P 3.7E−29 Human UbA52 placental mRNA for ubiquitin-52 amino acid fusion protein 3872 M00042536D:H05 MA167:E02 AF146019 gi|10197599|gb|AF146019.1AF146019   3E−26 Homo sapiens hepatocellular carcinoma antigen gene 520 mRNA, complete cds 3873 M00042465B:E04 MA171:E02 BC016732 gi|16876903|gb|BC016732.1BC016732 5.7E−202 Homo sapiens, thymosin, beta 4, X chromosome, clone MGC: 24503 IMAGE: 4096207, mRNA, complete cds 3874 M00042537D:F10 MA167:F02 BC000889 gi|12654142|gb|BC000889.1BC000889 1.6E−236 Homo sapiens, RNA polymerase I 16 kDa subunit, clone MGC: 4881 IMAGE: 3462906, mRNA, complete cds 3875 M00042467B:B04 MA171:F02 V00572 gi|35434|emb|V00572.1HSPGK1 Human   1E−240 mRNA encoding phosphoglycerate kinase 3876 M00042538D:D12 MA167:G02 X68195 gi|36165|emb|X68195.1HSRSPAC 6.6E−24 H. sapiens genomic DNA of ribosomal RNA intergenic spacer sequence 3877 M00042467B:B08 MA171:G02 U11861 gi|515482|gb|U11861.1HSU11861 Human 1.7E−165 G10 homolog (edg-2) mRNA, complete cds 3878 M00042711B:G09 MA167:B08 AF130094 gi|11493492|gb|AF130094.1AF130094   3E−207 Homo sapiens clone FLC0165 mRNA sequence 3879 M00042790B:E12 MA171:B08 AF039400 gi|4009457|gb|AF039400.1AF039400 5.9E−261 Homo sapiens calcium-dependent chloride channel-1 (hCLCA1) mRNA, complete cds 3880 M00042791A:C10 MA171:C08 NM_000147 gi|4503802|ref|NM_000147.1 Homo 1.3E−252 sapiens fucosidase, alpha-L-1, tissue (FUCA1), mRNA 3881 M00042711C:H05 MA167:D08 X16354 gi|37197|emb|X16354.1HSTM1CEA 2.7E−163 Human mRNA for transmembrane carcinoembryonic antigen BGPa (formerly TM1-CEA) 3882 M00042801D:B02 MA171:H08 BC002348 gi|12803088|gb|BC002348.1BC002348 4.9E−196 Homo sapiens, nuclear transport factor 2 (placental protein 15), clone MGC: 8327 IMAGE: 2819267, mR 3883 M00042801D:B02 MA171:H08 BC002348 gi|12803088|gb|BC002348.1BC002348 4.9E−196 Homo sapiens, nuclear transport factor 2 (placental protein 15), clone MGC: 8327 IMAGE: 2819267, mR 3884 M00056532A:D09 MA174:C02 0.78082 3885 M00056533D:H04 MA174:E02 AK000070 gi|7019918|dbj|AK000070.1AK000070 3.6E−287 Homo sapiens cDNA FLJ20063 fis, clone COL01524 3886 M00056575B:C04 MA174:B08 AK000113 gi|7019989|dbj|AK000113.1AK000113 2.4E−263 Homo sapiens cDNA FLJ20106 fis, clone COL04830 3887 M00056578C:A09 MA174:C08 NM_000988 gi|17017972|ref|NM_000988.2 Homo 2.1E−198 sapiens ribosomal protein L27 (RPL27), mRNA 3888 RG:1862072:20001:D08 MA139:D08 X61633 gi|37957|emb|X61633.1HSWIGEEX4 9.2E−25 H. sapiens Wilms tumor gene 1, exon 4 3889 RG:1862465:20001:F08 MA139:F08 0.81221 3890 RG:347381:10009:A02 MA158:A02 U38846 gi|1200183|gb|U38846.1HSU38846 0 Human stimulator of TAR RNA binding (SRB) mRNA, complete cds 3891 RG:417093:10009:D08 MA158:D08 0.08361 M17885 gi|190231|gb|M17885.1HUMPPARP0 4.4E−216 Human acidic ribosomal phosphoprotein P0 mRNA, complete cds 3892 M00043413B:C04 MA184:A02 AK027437 gi|14042109|dbj|AK027437.1AK027437 5.2E−174 Homo sapiens cDNA FLJ14531 fis, clone NT2RM2000371, weakly similar to POLYRIBONUCLEOTIDE NUCLEOT 3893 M00043502D:C12 MA184:F02 BC000820 gi|12654032|gb|BC000820.1BC000820 5.2E−252 Homo sapiens, menage a trois 1 (CAK assembly factor), clone MGC: 5154 IMAGE: 3453943, mRNA, complet 3894 M00057341B:B11 MA182:E08 BC001955 gi|12805002|gb|BC001955.1BC001955 1.1E−243 Homo sapiens, ribosomal protein S10, clone MGC: 4389 IMAGE: 2905318, mRNA, complete cds 3895 M00054512A:F11 MA184:G08 0.19488 3896 M00042353A:D05 MA182:H08 BC016352 gi|16741002|gb|BC016352.1BC016352   2E−123 Homo sapiens, small acidic protein, clone MGC: 24468 IMAGE: 4082845, mRNA, complete cds 3897 M00054937B:D09 MA198:B02 S79979 gi|1839333|gb|S79979.1S79979 ribosomal 2.8E−75 protein L37 [human, HeLa cells, Genomic/mRNA, 754 nt] 3898 M00055797C:H09 MA170:D08 BC009699 gi|16307220|gb|BC009699.1BC009699 8.2E−226 Homo sapiens, Similar to RNA helicase- related protein, clone MGC: 9246 IMAGE: 3892441, mRNA, comple 3899 M00055799B:C01 MA170:E08 X01117 gi|57149|emb|X01117.1RNRRNA06 Rat 1.5E−51 18S rRNA sequence 3900 M00055194C:G12 MA196:D02 BC008062 gi|14165518|gb|BC008062.1BC008062 7.7E−27 Homo sapiens, basic transcription factor 3, clone MGC: 2209 IMAGE: 2966788, mRNA, complete cds 3901 M00055233B:D08 MA196:B08 0.55474 3902 M00055966C:D06 MA179:H02 3903 M00056024B:B06 MA179:D08 BC011949 gi|15080385|gb|BC011949.1BC011949   6E−261 Homo sapiens, Similar to carbonic anhydrase II, clone MGC: 9006 IMAGE: 3863603, mRNA, complete cds 3904 M00056024C:G04 MA179:E08 3905 M00054737D:F10 MA188:D02 BC018828 gi|17402971|gb|BC018828.1BC018828 3.5E−284 Homo sapiens, clone IMAGE: 3343539, mRNA 3906 M00054780D:C09 MA188:A08 BC007967 gi|14044092|gb|BC007967.1BC007967 2.2E−151 Homo sapiens, clone MGC: 14460 IMAGE: 4304670, mRNA, complete cds 3907 M00054787A:E09 MA188:D08 NM_006013 gi|15718685|ref|NM_006013.2 Homo   8E−279 sapiens ribosomal protein L10 (RPL10), mRNA 3908 M00054806B:E11 MA188:E08 AK026650 gi|10439548|dbj|AK026650.1AK026650 1.3E−252 Homo sapiens cDNA: FLJ22997 fis, clone KAT11962, highly similar to HSEF1AC Human mRNA for elonga 3909 M00042913B:C11 MA168:B02 NM_000999 gi|16306562|ref|NM_000999.2 Homo 2.4E−182 sapiens ribosomal protein L38 (RPL38), mRNA 3910 M00042915B:B10 MA168:D02 AK058013 gi|16554011|dbj|AK058013.1AK058013 2.2E−201 Homo sapiens cDNA FLJ25284 fis, clone STM06787, highly similar to 15- HYDROXYPROSTAGLANDIN DEHYDR 3911 M00054792C:E12 MA168:E02 D14530 gi|414348|dbj|D14530.1HUMRSPT 4.1E−268 Human homolog of yeast ribosomal protein S28, complete cds 3912 M00042842A:C01 MA172:G02 0.66829 3913 M00055450A:C09 MA168:H08 0.8 3914 M00056804C:D01 MA175:H08 AF126743 gi|5052332|gb|AF126743.1AF126743 3.1E−278 Homo sapiens DNAJ domain-containing Protein MCJ (MCJ) mRNA, complete cds 3915 RG:1647954:10014:D08 MA163:D08 NM_001261 gi|17017983|ref|NM_001261.2 Homo 1.9E−273 sapiens cyclin-dependent kinase 9 (CDC2- related kinase) (CDK9), mRNA 3916 RG: 1664311:10014:F08 MA163:F08 X02761 gi|31396|emb|X02761.1HSFIB1 Human 0 mRNA for fibronectin (FN precursor) 3917 RG: 1671377:10014:G08 MA163:G08 BC013078 gi|15341811|gb|BC013078.1BC013078 2.8E−297 Homo sapiens, clone MGC: 17534 IMAGE: 3459415, mRNA, complete cds 3918 M00043316B:F10 MA183:C02 X16064 gi|37495|emb|X16064.1HSTUMP Human 2.7E−269 mRNA for translationally controlled tumor protein 3919 M00054545B:A03 MA185:D02 AF151048 gi|7106817|gb|AFl51048.1AF151048 4.6E−271 Homo sapiens HSPC214 mRNA, complete cds 3920 M00054545B:B09 MA185:E02 0.07415 X07979 gi|31441|emb|X07979.1HSFNRB Human 1.2E−126 mRNA for integrin beta 1 subunit 3921 M00054575A:B09 MA185:D08 X16064 gi|37495|emb|X16064.1HSTUMP Human 3.2E−278 mRNA for translationally controlled tumor protein 3922 M00043374B:H05 MA183:F08 0.11186 NM_053275 gi|16933545|ref|NM_053275.1 Homo   3E−136 sapiens ribosomal protein, large, P0 (RPLP0), transcript variant 2, mRNA 3923 M00056641A:G11 MA186:F02 BC003352 gi|13097158|gb|BC003352.1BC003352 3.6E−284 Homo sapiens, tumor protein, translationally-controlled 1, clone MGC: 5308 IMAGE: 2899964, mRNA, co 3924 M00056642A:D08 MA186:H02 0.78693 3925 M00055403B:B11 MA199:H02 NM_001021 gi|14591913|ref|NM_001021.2 Homo 5.8E−180 sapiens ribosomal protein S17 (RPS17), mRNA 3926 M00056676B:C11 MA186:H08 AF346968 gi|13272626|gb|AF346968.1AF346968 4.6E−165 Homo sapiens mitochondrion, complete genome 3927 M00055530D:B02 MA169:B03 NM_001012 gi|4506742|ref|NM_001012.1 Homo 1.5E−261 sapiens ribosomal protein S8 (RPS8), mRNA 3928 M00056253A:D06 MA181:C03 BC014166 gi|15559610|gb|BC014166.1BC014166 1.2E−274 Homo sapiens, clone IMAGE: 4549553, mRNA 3929 M00056253B:B06 MA181:D03 BC000053 gi|12652614|gb|BC000053.1BC000053 1.7E−270 Homo sapiens, LPS-induced TNF-alpha factor, clone IMAGE: 3506981, mRNA 3930 M00055642D:F09 MA169:D09 AF203815 gi|6979641|gb|AF203815.1AF203815 2.2E−257 Homo sapiens alpha gene sequence 3931 M00055643A:E09 MA169:E09 J03037 gi|179771|gb|J03037.1HUMCAIIA Human   3E−247 carbonic anhydrase II mRNA, complete cds 3932 M00055643D:E02 MA169:F09 M10050 gi|182355|gb|M10050.1HUMFABPL 2.1E−251 Human liver fatty acid binding protein (FABP) mRNA, complete cds 3933 M00055376D:D08 MA197:B09 D38112 gi|644480|dbj|D38112.1HUMMTA Homo 8.5E−111 sapiens mitochondrial DNA, complete sequence 3934 M00056415C:D02 MA173:B03 0.67751 3935 M00056146D:F05 MA180:B03 0.61693 3936 M00056417A:F02 MA173:C03 Z85099 gi|1834810|emb|Z85099.1HSZ85099 2.7E−31 H. sapiens Ig lambda light chain variable region gene (3-01OIIA11) rearranged; Ig- Light-Lambda; VLam 3937 M00056148A:B07 MA180:C03 AK026170 gi|10438933|dbj|AK026170.1AK026170 4.8E−134 Homo sapiens cDNA: FLJ22517 fis, clone HRC12186 3938 M00056420C:E07 MA173:D03 BC010735 gi|14789596|gb|BC010735.1BC010735 3.7E−262 Homo sapiens, Similar to eukaryotic translation elongation factor 1 alpha 1, clone MGC: 10096 IMAG 3939 M00056150A:E04 MA180:D03 0.82941 3940 M00056421C:H11 MA173:F03 X60489 gi|31099|emb|X60489.1HSEF1B Human 3.5E−228 mRNA for elongation factor-1-beta 3941 M00056150C:A10 MA180:F03 AL360191 gi|8919392|emb|AL360191.1HST000237 1.1E−237 Homo sapiens mRNA full length insert cDNA clone EUROIMAGE 781354 3942 M00056421D:H05 MA173:G03 BC017338 gi|16878283|gb|BC017338.1BC017338 1.1E−159 Homo sapiens, fucosidase, alpha-L-1, tissue, clone MGC: 29579 IMAGE: 4871788, mRNA, complete cds 3943 M00056150C:C04 MA180:G03 AJ276249 gi|7362984|emb|AJ276249.1HSA276249 1.3E−98 Homo sapiens partial mRNA, clone cl- 10e16 3944 M00056422B:D11 MA173:H03 BC001289 gi|12654890|gb|BC001289.1BC001289 1.9E−120 Homo sapiens, Sjogren syndrome antigen B (autoantigen La), clone MGC: 5194 IMAGE: 3454454, mRNA, co 3945 M00056151C:A12 MA180:H03 X59706 gi|34204|emb|X59706.1HSLA1L1IG 1.5E−227 H. sapiens rearranged Humigla1L1 gene encoding IgG light chain 3946 M00056493C:E06 MA173:A09 AF153608 gi|5231140|gb|AF153608.1AF153608 1.3E−280 Homo sapiens sin3 associated polypeptide (SAP18) mRNA, complete cds 3947 M00056205D:E03 MA180:A09 0.78241 3948 M00056495A:G10 MA173:B09 M63573 gi|337998|gb|M63573.1HUMSCYLP 4.5E−100 Human secreted cyclophilin-like protein (SCYLP) mRNA, complete cds 3949 M00056206D:B10 MA180:E09 AF001893 gi|2529723|gb|AF001893.1BETA2 Human 1.1E−35 MEN1 region clone epsilon/beta mRNA, 3′ fragment 3950 M00056501D:C08 MA173:H09 Y11339 gi|7576275|emb|Y11339.2HSY11339 1.9E−220 Homo sapiens mRNA for GalNAc alpha-2, 6-sialyltransferase I, long form 3951 M00056209D:H10 MA180:H09 0.08151 J03037 gi|179771|gb|J03037.1HUMCAIIA Human 1.6E−258 carbonic anhydrase II mRNA, complete cds 3952 M00054645B:C12 MA187:B03 0.18868 BC008092 gi|14198047|gb|BC008092.1BC008092 7.3E−105 Homo sapiens, ribosomal protein, large, P0, clone MGC: 9343 IMAGE: 3458803, mRNA, complete cds 3953 M00054646A:B10 MA187:C03 BC007097 gi|13937968|gb|BC007097.1BC007097 5.2E−146 Homo sapiens, tissue inhibitor of metalloproteinase 1 (erythroid potentiating activity, collagena 3954 M00054647D:E01 MA187:G03 NM_001026 gi|14916502|ref|NM_001026.2 Homo 6.4E−111 sapiens ribosomal protein S24 (RPS24), transcript variant 2, mRNA 3955 M00057202C:G06 MA193:E03 3956 M00057202D:C11 MA193:F03 X71973 gi|311699|emb|X71973.1HSGPX4 1.3E−26 H. sapiens GPx-4 mRNA for phospholipid hydroperoxide glutathione peroxidase 3957 M00042549A:G12 MA167:C03 AF153609 gi|5231142|gb|AF153609.1A1F153609 1.8E−120 Homo sapiens serine/threonine protein kinase sgk mRNA, complete cds 3958 M00042549D:F03 MA167:D03 BC011025 gi|15029635|gb|BC011025.1BC011025 6.8E−34 Homo sapiens, Similar to sorcin, clone MGC: 13597 IMAGE: 4281626, mRNA, complete cds 3959 M00042551B:D12 MA167:E03 NM_002295 gi|9845501|ref|NM_002295.2 Homo 8.3E−226 sapiens laminin receptor 1 (67 kD, ribosomal protein SA) (LAMR1), mRNA 3960 M00042513A:D03 MA171:E03 NM_001002 gi|16933547|ref|NM_001002.2 Homo 2.5E−266 sapiens ribosomal protein, large, P0 (RPLP0), transcript variant 1, mRNA 3961 M00042513D:A12 MA171:F03 0.53205 3962 M00042551D:D12 MA167:H03 Z48514 gi|695600|emb|Z48514.1HSXGR4551 2.8E−191 H. sapiens XG mRNA (clone R4(551)) 3963 M00042717B:D05 MA167:A09 0.47619 X98311 gi|1524059|emb|X98311.1HSCGM2ANT 1.1E−45 H. sapiens mRNA for carcinoembryonic antigen family member 2, CGM2 3964 M00042719D:C09 MA167:B09 L31792 gi|471076|gb|L31792.1HUMCGM2A 4.2E−144 Homo sapiens carcinoembryonic antigen (CGM2) mRNA, complete cds 3965 M00042803C:F11 MA171:C09 M31520 gi|337504|gb|M31520.1HUMRPS24A 7.6E−120 Human ribosomal protein S24 mRNA 3966 M00042805D:D12 MA171:E09 BC004324 gi|13279235|gb|BC004324.1BC004324 2.4E−263 Homo sapiens, ribosomal protein S16, clone MGC: 10931 IMAGE: 3628799, mRNA, complete cds 3967 M00042731A:G04 MA167:F09 Z84867 gi|1834578|emb|Z84867.1HSZ84867 5.8E−113 H. sapiens Ig lambda light chain variable region gene (14-09DPIA215) rearranged; Ig-Light-Lambda; VL 3968 M00042806C:E09 MA171:G09 0.12055 U16738 gi|608516|gb|U16738.1HSU16738 Homo 1.4E−165 sapiens CAG-isl 7 mRNA, complete cds 3969 M00042806D:F08 MA171:H09 Y16241 gi|3378195|emb|Y16241.1HSY16241   3E−247 Homo sapiens mRNA for nebulette 3970 M00056537A:F05 MA174:C03 NM_021130 gi|10863926|ref|NM_021130.1 Homo 5.1E−249 sapiens peptidylprolyl isomerase A (cyclophilin A) (PPIA), mRNA 3971 M00056537D:A07 MA174:D03 BC019255 gi|17939424|gb|BC019255.1BC019255 2.3E−260 Homo sapiens, multifunctional polypeptide similar to SAICAR synthetase and AIR carboxylase, clone 3972 RG:1862584:20001:G03 MA139:G03 0.72829 3973 M00056585D:D05 MA174:A09 BC007989 gi|14124931|gb|BC007989.1BC007989 1.3E−283 Homo sapiens, Similar to heat shock 90 kD protein 1, alpha, clone IMAGE: 3030617, mRNA, partial cds 3974 M00056586C:B08 MA174:B09 BC013873 gi|15530196|gb|BC013873.1BC013873 1.2E−184 Homo sapiens, Similar to centrin, EF-hand protein, 2, clone MGC: 10365 IMAGE: 3836808, mRNA, comple 3975 M00056592A:B08 MA174:E09 AB018580 gi|6624210|dbj|AB018580.1AB018580 7.8E−251 Homo sapiens mRNA for hluPGFS, complete cds 3976 RG:378550:10009:C03 MA158:C03 3977 RG:789040:10011:F09 MA160:F09 M14676 gi|338227|gb|M14676.1HUMSLK Human   1E−300 src-like kinase (slk) mRNA, complete cds 3978 M00057283A:D01 MA182:B03 AF283772 gi|10281741|gb|AF283772.2AF283772 2.5E−266 Homo sapiens clone TCBAP0781 mRNA sequence 3979 M00043505A:E07 MA184:D03 NM_007209 gi|16117792|ref|NM_007209.2 Homo 5.5E−258 sapiens ribosomal protein L35 (RPL35), mRNA 3980 M00043506B:G10 MA184:G03 BC007945 gi|14044036|gb|BC007945.1BC007945   1E−197 Homo sapiens, ribosomal protein S11, clone MGC: 14322 IMAGE: 4297932, mRNA, complete cds 3981 M00043507A:B02 MA184:H03 3982 M00042353C:F02 MA182:A09 NM_001015 gi|14277698|ref|NM_001015.2 Homo 3.4E−256 sapiens ribosomal protein S11 (RPS11), mRNA 3983 M00054516B:A08 MA184:F09 BC004459 gi|13325289|gb|BC004459.1BC004459   5E−280 Homo sapiens, eukaryotic translation initiation factor 4E binding protein 1, clone MGC: 4316 IMAGE 3984 M00054986D:B04 MA198:A09 AJ131712 gi|7576251|emb|AJ131712.1HSA131712 1.2E−168 Homo sapiens mRNA for nucleolar RNA- helicase (noH61 gene) 3985 M00054987C:B10 MA198:B09 0.09792 AF097362 gi|6165617|gb|AF097362.1AF097362 9.1E−139 Homo sapiens gamma-interferon inducible lysosomal thiol reductase (GILT) mRNA, complete cds 3986 M00054988D:B11 MA198:C09 BC019051 gi|17403061|gb|BC019051.1BC019051 1.8E−192 Homo sapiens, clone IMAGE: 4636237, mRNA 3987 M00055743C:G08 MA170:E03 BC018970 gi|17512000|gb|BC018970.1BC018970 2.8E−216 Homo sapiens, ribosomal protein L11, clone MGC: 19586 IMAGE: 4337066, mRNA, complete cds 3988 M00055196B:C09 MA196:D03 BC018755 gi|17511806|gb|BC018755.1BC018755 6.7E−242 Homo sapiens, PDZ and LIM domain 1 (elfin), clone MGC: 31954 IMAGE: 3610938, mRNA, complete cds 3989 M00055238B:G05 MA196:B09 NM_012423 gi|14591905|ref|NM_012423.2 Homo 3.8E−206 sapiens ribosomal protein L13a (RPL13A), mRNA 3990 M00056207B:H06 MA180:G09 0.89703 3991 M00055966C:G04 MA179:A03 BC008492 gi|14250147|gb|BC008492.1BC008492 8.2E−282 Homo sapiens, ribosomal protein L3, clone MGC: 14821 IMAGE: 4251511, mRNA, complete cds 3992 M00056920D:C08 MA177:A03 BC014301 gi|15679985|gb|BC014301.1BC014301 8.8E−204 Homo sapiens, Similar to enhancer of rudimentary (Drosophila) homolog, clone MGC: 1509 IMAGE: 35072 3993 M00055969D:D01 MA179:C03 0.16904 X73501 gi|402644|emb|X73501.1HSCYTOK20   4E−225 H. sapiens gene for cytokeratin 20 3994 M00056055D:F06 MA179:E09 AY011168 gi|12699140|gb|AY011168.1 Homo 5.4E−149 sapiens 16S ribosomal RNA gene, partial sequence; mitochondrial gene for mitochondrial product 3995 M00056956B:G12 MA177:E09 0.87013 3996 M00056060D:C04 MA179:F09 V00710 gi|13683|emb|V00710.1MIT1HS Human   4E−184 mitochondrial genes for several tRNAs (Phe, Val, Leu) and 12S and 16S ribosomal RNAs 3997 M00056061C:H04 MA179:G09 U14528 gi|549987|gb|U14528.1HSU14528 Human 3.4E−219 sulfate transporter (DTD) mRNA, complete cds 3998 M00054743C:E05 MA188:A03 BC001603 gi|12804402|gb|BC001603.1BC001603 2.3E−179 Homo sapiens, Similar to ribosomal protein L21, clone MGC: 2150 IMAGE: 3543702, mRNA, complete cds 3999 M00054744C:B02 MA188:B03 NM_033643 gi|16117795|ref|NM_033643.1 Homo 6.2E−92 sapiens ribosomal protein L36 (RPL36), transcript variant 1, mRNA 4000 M00054808A:E02 MA188:C09 BC003030 gi|12804340|gb|BC003030.1BC003030 5.5E−174 Homo sapiens, heat shock 60 kD protein 1 (chaperonin), clone MGC: 4335 IMAGE: 2821157, mRNA, complet 4001 M00054811A:G01 MA188:G09 X90583 gi|1071680|emb|X90583.1HSRNATRAP 3.9E−184 H. sapiens mRNA for rat translocon- associated protein delta homolog 4002 M00054797C:G10 MA168:A03 BC004983 gi|13436415|gb|BC004983.1BC004983 2.1E−148 Homo sapiens, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha 4003 M00042843B:H01 MA172:A03 AF068754 gi|3283408|gb|AF068754.1AF068754 7.8E−139 Homo sapiens heat shock factor binding protein 1 HSBP1 mRNA, complete cds 4004 M00042844D:D10 MA172:D03 BC000483 gi|12653424|gb|BC000483.1BC000483 2.3E−232 Homo sapiens, clone MGC: 8704 IMAGE: 2964733, mRNA, complete cds 4005 M00042845D:A12 MA172:E03 BC008329 gi|14249899|gb|BC008329.1BC008329 8.5E−229 Homo sapiens, clone MGC: 15787 IMAGE: 3504130, mRNA, complete cds 4006 M00054800C:H10 MA168:G03 Z85052 gi|1834763|emb|Z85052.1HSZ85052   9E−167 H. sapiens Ig lambda light chain variable region gene (26-34ITIIIF120) rearranged; Ig-Light-Lambda; 4007 M00054911D:E09 MA168:H03 NM_000969 gi|14591908|ref|NM_000969.2 Homo 7.2E−217 sapiens ribosomal protein L5 (RPL5), mRNA 4008 M00055450A:G03 MA168:A09 0.09821 AF074331 gi|5052074|gb|AF074331.1AF074331 6.8E−152 Homo sapiens PAPS synthetase-2 (PAPSS2) mRNA, complete cds 4009 M00055456B:H05 MA168:D09 0.79701 4010 M00056733C:D03 MA175:D03 X97336 gi|1666193|emb|X97336.1RUMTGENOM 3.1E−72 Rhinoceros unicornis complete mitochondrial genome 4011 M00056737D:E08 MA175:H03 D11094 gi|219930|dbj|D11094.1HUMMSS1 5.9E−230 Human mRNA for MSS1, complete cds 4012 M00056809B:A12 MA175:E09 L42345 gi|1160933|gb|L42345.1HUMHLAB44A   6E−152 Homo sapiens lymphocyte antigen HLA- B*4402 and HLA-B*5101 mRNA, exons 1-7, complete cds 4013 M00056809D:C07 MA175:G09 J03801 gi|187243|gb|J03801.1HUMLSZ Human 9.3E−207 lysozyme mRNA, complete cds with an Alu repeat in the 3′ flank 4014 RG:1664308:10014:F09 MA163:F09 AF011497 gi|2286216|gb|AF011497.1AF011497 0 Homo sapiens guanine nucleotide binding protein alpha 11 subunit (G11) mRNA, complete cds 4015 M00043321A:G07 MA183:B03 D49400 gi|1395161|dbj|D49400.1HUMVATPASE 5.1E−280 Homo sapiens mRNA for vacuolar ATPase, complete cds 4016 M00054549A:F03 MA185:C03 0.84052 4017 M00043381A:C08 MA183:D09 NM_001012 gi|4506742|ref|NM_001012.1 Homo 1.1E−231 sapiens ribosomal protein S8 (RPS8), mRNA 4018 M00056642B:G03 MA186:A03 BC010952 gi|15012094|gb|BC010952.1BC010952   1E−300 Homo sapiens, Similar to protease inhibitor 3, skin-derived (SKALP), clone MGC: 13613 IMAGE: 408315 4019 M00056688C:A07 MA186:H09 D13748 gi|219402|dbj|D13748.1HUM4AI Human   1E−300 mRNA for eukaryotic initiation factor 4AI 4020 M00056257C:G03 MA181:A04 AK054673 gi|16549265|dbj|AK054673.1AK054673 3.6E−228 Homo sapiens cDNA FL130111 fis, clone BNGH42000360, highly similar to 3- KETOACYL-COA THIOLASE MI 4021 M00055545C:F11 MA169:G04 AY029066 gi|14017398|gb|AY029066.1 Homo 1.4E−258 sapiens Humanin (HN1) mRNA, complete cds 4022 M00055653C:F04 MA169:C10 M10050 gi|182355|gb|M10050.1HUMFABPL   5E−224 Human liver fatty acid binding protein (FABP) mRNA, complete cds 4023 M00055653D:F01 MA169:D10 M10050 gi|182355|gb|M10050.1HUMFABPL 1.9E−167 Human liver fatty acid binding protein (FABP) mRNA, complete cds 4024 M00055385A:C11 MA197:B10 BC013231 gi|15301504|gb|BC013231.1BC013231 2.9E−244 Homo sapiens, clone IMAGE: 3462987, mRNA 4025 M00056157A:F11 MA180:D04 X74104 gi|452756|emb|X74104.1HSSSR H. sapiens 4.5E−274 mRNA for TRAP beta subunit 4026 M00056160A:F03 MA180:E04 0.89209 4027 M00056426A:H07 MA173:F04 0.49541 4028 M00056214C:B04 MA180:C10 Y00339 gi|29586|emb|Y00339.1HSCA2 Human   3E−222 mRNA for carbonic anhydrase II (EC 4.2.1.1) 4029 M00056216A:F10 MA180:D10 0.75335 4030 M00056507A:G11 MA173:G10 0.71615 4031 M00054648C:C10 MA187:A04 BC004113 gi|13278665|gb|BC004113.1BC004113 1.6E−236 Homo sapiens, Similar to non-POU- domain-containing, octamer-binding, clone IMAGE: 3835400, mRNA, p 4032 M00054862A:H11 MA189:A04 0.60181 4033 M00054648D:F12 MA187:B04 BC001118 gi|12654566|gb|BC001118.1BC001118 1.5E−289 Homo sapiens, Similar to seven transmembrane domain protein, clone MGC: 1936 IMAGE: 2989840, mRNA, 4034 M00054650C:H08 MA187:D04 AB026723 gi|5931601|dbj|AB026723.1AB026723 1.6E−295 Homo sapiens SID6-8061 mRNA for pyrophosphatase, complete cds 4035 M00054868C:C11 MA189:H04 0.09703 4036 M00054700C:E02 MA187:D10 BC000530 gi|12653516|gb|BC000530.1BC000530 2.9E−244 Homo sapiens, ribosomal protein L19, clone MGC: 8653 IMAGE: 2961653, mRNA, complete cds 4037 M00054902D:G11 MA189:F10 0.71088 4038 M00054903B:G06 MA189:G10 BC013231 gi|15301504|gb|BC013231.1BC013231 1.1E−240 Homo sapiens, clone IMAGE: 3462987, mRNA 4039 M00054706A:D05 MA187:H10 AB060236 gi|13676490|dbj|AB060236.1AB060236 6.9E−71 Macaca fascicularis brain cDNA clone: QflA-11918, full insert sequence 4040 M00057207A:D05 MA193:C04 AF127763 gi|6138993|gb|AF127763.2AF127763 2.7E−297 Homo sapiens mitogenic oxidase mRNA, complete cds 4041 M00057207C:F06 MA193:D04 BC016756 gi|16876963|gb|BC016756.1BC016756 9.4E−291 Homo sapiens, glutathione peroxidase 2 (gastrointestinal), clone IMAGE: 3681457, mRNA 4042 M00057208B:F11 MA193:F04 X60489 gi|31099|emb|X60489.1HSEF1B Human   8E−279 mRNA for elongation factor-1-beta 4043 M00057242B:B10 MA193:C10 J03464 gi|179595|gb|J03464.1HUMC1A2 Human 2.1E−282 collagen alpha-2 type I mRNA, complete cds, clone pHCOL2A1 4044 M00042555A:E06 MA167:C04 0.79249 4045 M00042561A:H03 MA167:D04 AK057546 gi|16553292|dbj|AK057546.1AK057546 3.1E−278 Homo sapiens cDNA FLJ32984 fis, clone THYMU1000017, highly similar to Homo sapiens splice varian 4046 M00042756C:E10 MA171:E04 NM_005348 gi|13129149|ref|NM_005348.1 Homo   3E−222 sapiens heat shock 90 kD protein 1, alpha (HSPCA), mRNA 4047 M00042758D:F01 MA171:F04 NM_000969 gi|14591908|ref|NM_000969.2 Homo 3.7E−259 sapiens ribosomal protein L5 (RPL5), mRNA 4048 M00042759B:E02 MA171:H04 BC000077 gi|12652658|gb|BC000077.1BC000077 5.1E−252 Homo sapiens, ribosomal protein L8, clone MGC: 3253 IMAGE: 3506015, mRNA, complete cds 4049 M00042808D:D03 MA171:B10 AB048207 gi|15425668|dbj|AB048207.1AB048207 2.2E−257 Homo sapiens mRNA for TIGA1, complete cds 4050 M00042808D:D10 MA171:C10 AK026166 gi|10438929|dbj|AK026166.1AK026166 9.5E−263 Homo sapiens cDNA: FLJ22513 fis, clone HRC12111, highly similar to HUMKUP Human Ku (p70/p80) sub 4051 M00042811B:A05 MA171:D10 AK027191 gi|10440260|dbj|AK027191.1AK027191 1.6E−121 Homo sapiens cDNA: FLJ23538 fis, clone LNG08010, highly similar to BETA2 Human MEN1 region clone 4052 M00042746B:F05 MA167:E10 AK026528 gi|10439405|dbj|AK026528.1AK026528 1.6E−77 Homo sapiens cDNA: FLJ22875 fis, clone KAT02879 4053 M00042746C:D01 MA167:G10 BC000551 gi|12653554|gb|BC000551.1BC000551   5E−128 Homo sapiens, lysophospholipase-like, clone MGC: 1216 IMAGE: 3163689, mRNA, complete cds 4054 M00042812D:B04 MA171:G10 NM_000978 gi|14591907|ref|NM_000978.2 Homo 3.5E−256 sapiens ribosomal protein L23 (RPL23), mRNA 4055 M00056546B:F12 MA174:A04 AK026570 gi|10439452|dbj|AK026570.1AK026570 2.1E−226 Homo sapiens cDNA: FLJ22917 fis, clone KAT06430 4056 M00056550A:G09 MA174:H04 X14420 gi|30057|emb|X14420.1HSCOL3AI 5.1E−165 Human mRNA for pro-alpha-1 type 3 collagen 4057 M00056610C:B08 MA174:G10 D87667 gi|1620019|dbj|D87667.1D87667 Human 1.4E−199 brain mRNA homologous to 3′UTR of human CD24 gene, partial sequence 4058 RG:745556:10011:B04 MA160:B04 AK056676 gi|16552146|dbj|AK056676.1AK056676 8.7E−227 Homo sapiens cDNA FLJ32114 fis, clone OCBBF2001706 4059 RG:446537:10009:G04 MA158:G04 BC001430 gi|12655150|gb|BC001430.1BC001430 0 Homo sapiens, POP7 (processing of precursor, S. cerevisiae) homolog, clone MGC: 1986 IMAGE: 3138336 4060 RG:375937:10009:B10 MA158:B10 BC010153 gi|14603405|gb|BC010153.1BC010153 1.1E−77 Homo sapiens, cyclin-dependent kinase 4, clone MGC: 19704 IMAGE: 3531300, mRNA, complete cds 4061 RG:755120:10011:B10 MA160:B10 BC016725 gi|16876888|gb|BC016725.1BC016725 3.5E−52 Homo sapiens, 60S ribosomal protein L30 isolog, clone MGC: 24451 IMAGE: 4078305, mRNA, complete cds 4062 RG:781108:10011:D10 MA160:D10 4063 M00042450C:H10 MA182:A10 S56985 gi|298485|gb|S56985.1S56985 ribosomal 1.4E−258 protein L19 [human, breast cancer cell line, MCF-7, mRNA, 690 nt] 4064 M00042451B:B05 MA182:B10 BC013231 gi|15301504|gb|BC013231.1BC013231 1.7E−239 Homo sapiens, clone IMAGE: 3462987, mRNA 4065 M00054517D:D12 MA184:B10 NM_000661 gi|15431302|ref|NM_000661.2 Homo   1E−156 sapiens ribosomal protein L9 (RPL9), mRNA 4066 M00055002B:G06 MA198:D10 J04164 gi|177801|gb|J04164.1HUM927A Human 1.5E−177 interferon-inducible protein 9-27 mRNA, complete cds 4067 M00055749A:C09 MA170:B04 0.08723 M36532 gi|179794|gb|M36532.1HUMCAIZ Human 1.8E−236 carbonic anhydrase II mRNA, complete cds 4068 M00055750A:F10 MA170:D04 X57809 gi|33714|emb|X57809.1HSIGVL009 4.1E−178 Human rearranged immunoglobulin lambda light chain mRNA 4069 M00055757A:H06 MA170:G04 M12759 gi|532596|gb|M12759.1HUMIGJ02 2.6E−104 Human Ig J chain gene, exons 3 and 4 4070 M00055200B:F03 MA196:D04 AK056446 gi|16551850|dbj|AK056446.1AK056446 2.3E−232 Homo sapiens cDNA FLJ31884 fis, clone NT2RP7002906, highly similar to HEAT SHOCK PROTEIN HSP 90- 4071 M00055203B:F05 MA196:F04 NM_000979 gi|15431298|ref|NM_000979.2 Homo 3.8E−262 sapiens ribosomal protein L18 (RPL18), mRNA 4072 M00055980B:F12 MA179:E04 AK000140 gi|7020034|dbj|AK000140.1AK000140 6.8E−270 Homo sapiens cDNA FLJ20133 fis, clone COL06539 4073 M00056066C:H10 MA179:B10 0.89137 4074 M00056067B:F12 MA179:C10 BC011836 gi|15080121|gb|BC011836.1BC011836 7.1E−273 Homo sapiens, clone IMAGE: 3945177, mRNA 4075 M00056075D:H10 MA179:D10 AK027140 gi|10440192|dbj|AK027140.1AK027140 3.3E−200 Homo sapiens cDNA: FLJ23487 fis, clone LNG00423 4076 M00056962D:A05 MA177:D10 BC017366 gi|16924194|gb|BC017366.1BC017366 2.4E−91 Homo sapiens, clone MGC: 1191 IMAGE: 3506054, mRNA, complete cds 4077 M00056081D:B09 MA179:E10 AF346964 gi|13272570|gb|AF346964.1AF346964 1.9E−93 Homo sapiens mitochondrion, complete genome 4078 M00056963A:E01 MA177:E10 BC000999 gi|12803040|gb|BC000999.2BC000999 1.9E−276 Homo sapiens, Similar to transforming, acidic coiled-coil containing protein 2, clone IMAGE: 29849 4079 M00056081D:C02 MA179:F10 V00710 gi|13683|emb|V00710.1MIT1HS Human 1.3E−97 mitochondrial genes for several tRNAs (Phe, Val, Leu) and 12S and 16S ribosomal RNAs 4080 M00056964D:C08 MA177:G10 M36072 gi|337494|gb|M36072.1HUMRPL7A 1.8E−245 Human ribosomal protein L7a (surf 3) large subunit mRNA, complete cds 4081 M00056084A:B08 MA179:H10 U67963 gi|1763010|gb|U67963.1HSU67963 2.3E−136 Human lysophospholipase homolog (HU- K5) mRNA, complete cds 4082 M00054750C:G08 MA188:B04 BC001125 gi|12654578|gb|BC001125.1BC001125 1.1E−190 Homo sapiens, peptidylprolyl isomerase B (cyclophilin B), clone MGC: 2224 IMAGE: 2966791, mRNA, com 4083 M00054750D:F04 MA188:C04 U30246 gi|903681|gb|U30246.1HSU30246 Human   3E−247 bumetanide-sensitive Na-K-Cl cotransporter (NKCC1) mRNA, complete cds 4084 M00054757A:F05 MA188:G04 U86602 gi|1835785|gb|U86602.1HSU86602   1E−300 Human nucleolar protein p40 mRNA, complete cds 4085 M00054760D:B10 MA188:H04 BC014788 gi|15928638|gb|BC014788.1BC014788   1E−300 Homo sapiens, guanine nucleotide binding protein (G protein), beta polypeptide 2-like 1, clone MG 4086 M00042847A:A04 MA172:A04 M61831 gi|178276|gb|M61831.1HUMAHCY 5.5E−230 Human S-adenosylhomocysteine hydrolase (AHCY) mRNA, complete cds 4087 M00042847A:D10 MA172:B04 0.82393 4088 M00054917B:G02 MA168:F04 J04164 gi|177801|gb|J04164.1HUM927A Human 6.4E−239 interferon-inducible protein 9-27 mRNA, complete cds 4089 M00055468D:D05 MA168:C10 BC001781 gi|12804704|gb|BC001781.1BC001781 2.2E−173 Homo sapiens, ribosomal protein L44, clone MGC: 2064 IMAGE: 3353669, mRNA, complete cds 4090 M00055469B:E11 MA168:D10 0.52048 U07969 gi|483391|gb|U07969.1HSU07969 Human 7.2E−103 intestinal peptide-associated transporter HPT-1 mRNA, complete cds 4091 M00055492C:C01 MA168:G10 BC003394 gi|13097278|gb|BC003394.1BC003394 3.2E−253 Homo sapiens, heterogeneous nuclear ribonucleoprotein C (C1/C2), clone MGC: 5418 IMAGE: 3447724, mR 4092 M00055496A:E06 MA168:H10 0.86834 4093 M00056742D:D01 MA175:F04 U51924 gi|1263307|gb|U51924.1HSU51924 1.3E−199 Human phosphatase 2A inhibitor I2PP2A mRNA, complete cds 4094 M00056814D:C08 MA175:G10 BC000472 gi|12653404|gb|BC000472.1BC000472 2.4E−291 Homo sapiens, ribosomal protein S4, X- linked, clone MGC: 8636 IMAGE: 2961540, mRNA, complete cds 4095 RG:1636303:10014:B10 MA163:B10 AJ338808 gi|15883226|emb|AJ338808.1HSA338808 0 Homo sapiens genomic sequence surrounding NotI site, clone NR1-QA13R 4096 RG:1643142:10014:C10 MA163:C10 U14528 gi|549987|gb|U14528.1HSU14528 Human 5.6E−138 sulfate transporter (DTD) mRNA, complete cds 4097 RG:1650444:10014:D10 MA163:D10 D10040 gi|219899|dbj|D10040.1HUMLCACS 0 Homo sapiens mRNA for long-chain acyl- CoA synthetase, complete cds 4098 RG:1418984:10003:H10 MA152:H10 X52967 gi|36139|emb|X52967.1HSRPL7 Human   1E−300 mRNA for ribosomal protein L7 4099 M00043339C:C12 MA183:A04 X60489 gi|31099|emb|X60489.1HSEF1B Human   7E−270 mRNA for elongation factor-1-beta 4100 M00043342C:H03 MA183:B04 AK026558 gi|10439440|dbj|AK026558.1AK026558 4.1E−159 Homo sapiens cDNA: FLJ22905 fis, clone KAT05654, highly similar to HUMRPL18A Homo sapiens riboso 4101 M00043350A:C04 MA183:D04 BC004324 gi|13279235|gb|BC004324.1BC004324 3.7E−231 Homo sapiens, ribosomal protein S16, clone MGC: 10931 IMAGE: 3628799, mRNA, complete cds 4102 M00056646D:G05 MA186:B04 BC018190 gi|17390422|gb|BC018190.1BC018190 3.4E−172 Homo sapiens, Similar to metallothionein 1L, clone MGC: 9187 IMAGE: 3859643, mRNA, complete cds 4103 M00055406C:H08 MA199:D04 AF078861 gi|5531836|gb|AF078861.1AF078861 1.8E−192 Homo sapiens PTD008 mRNA, complete cds 4104 M00056653C:F06 MA186:H04 BC005354 gi|13529169|gb|BC005354.1BC005354 1.6E−264 Homo sapiens, ribosomal protein, large P2, clone MGC: 12453 IMAGE: 4052568, mRNA, complete cds 4105 M00055408A:H06 MA199:H04 AF054183 gi|4092053|gb|AF054183.1AF054183   1E−187 Homo sapiens GTP binding protein mRNA, complete cds 4106 M00055545D:E02 MA169:A05 BC009699 gi|16307220|gb|BC009699.1BC009699   5E−224 Homo sapiens, Similar to RNA helicase- related protein, clone MGC: 9246 IMAGE: 3892441, mRNA, comple 4107 M00055548B:H07 MA169:C05 AF105253 gi|7532779|gb|AF105253.1AF105253 4.2E−268 Homo sapiens neuroendocrine secretory protein 55 mRNA, complete cds 4108 M00056271C:F02 MA181:D05 BC008323 gi|14249887|gb|BC008323.1BC008323 5.8E−202 Homo sapiens, clone MGC: 15764 IMAGE: 3358085, mRNA, complete cds 4109 M00055550D:A05 MA169:F05 AF130094 gi|11493492|gb|AF130094.1AF130094 3.4E−225 Homo sapiens clone FLC0165 mRNA sequence 4110 M00055661A:F09 MA169:E11 4111 M00056427D:A09 MA173:B05 U07550 gi|469170|gb|U07550.1HSU07550 Human   2E−145 chaperonin 10 mRNA, complete cds 4112 M00056163C:H09 MA180:B05 AF201944 gi|9295191|gb|AF201944.1AF201944 2.2E−285 Homo sapiens HGTD-P (HGTD-P) mRNA, complete cds 4113 M00056428B:F07 MA173:C05 U30246 gi|903681|gb|U30246.1HSU30246 Human 9.7E−126 bumetanide-sensitive Na—K—Cl cotransporter (NKCC1) mRNA, complete cds 4114 M00056163D:E01 MA180:C05 BC001829 gi|12804776|gb|BC001829.1BC001829 4.4E−240 Homo sapiens, lactate dehydrogenase A, clone MGC: 4065 IMAGE: 2960999, mRNA, complete cds 4115 M00056428C:A12 MA173:E05 NM_001016 gi|14277699|ref|NM_001016.2 Homo 4.2E−212 sapiens ribosomal protein S12 (RPS12), mRNA 4116 M00056429D:D07 MA173:F05 0.53763 4117 M00056175D:B05 MA180:G05 Z62862 gi|1035240|emb|Z62862.1HS74B1R 6.9E−87 H. sapiens CpG island DNA genomic Mse1 fragment, clone 74b1, reverse read cpg74b1.rt1a 4118 M00056507D:D04 MA173:A11 0.65197 4119 M00056511D:H07 MA173:F11 BC000419 gi|12653300|gb|BC000419.1BC000419 6.1E−205 Homo sapiens, catechol-O- methyltransferase, clone MGC: 8663 IMAGE: 2964400, mRNA, complete cds 4120 M00054654A:F12 MA187:A05 NM_000976 gi|15431291|ref|NM_000976.2 Homo   1E−296 sapiens ribosomal protein L12 (RPL12), mRNA 4121 M00054868D:F12 MA189:A05 NM_012423 gi|14591905|ref|NM_012423.2 Homo 4.4E−140 sapiens ribosomal protein L13a (RPL13A), mRNA 4122 M00054661B:H10 MA187:D05 L47277 gi|986911|gb|L47277.1HUMTOPATRA 5.8E−261 Homo sapiens (cell line HepG2, HeLa) alpha topoisomerase truncated-form mRNA, 3′UTR 4123 M00054666B:C07 MA187:F05 AJ250229 gi|8926686|emb|AJ250229.1HSA250229 6.1E−205 Homo sapiens mRNA for chromosome 11 hypothetical protein (ORF1) 4124 M00054870B:H05 MA189:F05 M26326 gi|186690|gb|M26326.1HUMKER18AA 4.8E−121 Human keratin 18 mRNA, complete cds 4125 M00054669B:B03 MA187:G05 BC001754 gi|12804658|gb|BC001754.1BC001754   8E−192 Homo sapiens, male-enhanced antigen, clone MGC: 2286 IMAGE: 3355279, mRNA, complete cds 4126 M00054706B:G04 MA187:A11 AF201944 gi|9295191|gb|AF201944.1AF201944 8.3E−251 Homo sapiens HGTD-P (HGTD-P) mRNA, complete cds 4127 M00054720C:F01 MA187:D11 BC013918 gi|15530264|gb|BC013918.1BC013918 1.4E−224 Homo sapiens, Similar to eukaryotic translation elongation factor 1 gamma, clone MGC: 22883 IMAGE: 4128 M00054722B:E08 MA187:E11 Z62862 gi|1035240|emb|Z62862.1HS74B1R   6E−116 H. sapiens CpG island DNA genomic Mse1 fragment, clone 74b1, reverse read cpg74b1.rt1a 4129 M00054908A:H08 MA189:E11 L00160 gi|189904|gb|L00160.1HUMPGK2 Human 2.4E−291 phosphoglycerate kinase (pgk) mRNA, exons 2 to last 4130 M00054723B:H12 MA187:G11 X60819 gi|34458|emb|X60819.1HSMAOP14 1.6E−295 H. sapiens DNA for monoamine oxidase type A (14) (partial) 4131 M00057210B:G10 MA193:C05 U12404 gi|5311701|gb|U12404.1HSU12404 Human 3.5E−175 Csa-19 mRNA, complete cds 4132 M00057248D:B05 MA193:B11 NM_001024 gi|14670385|ref|NM_001024.2 Homo 1.3E−196 sapiens ribosomal protein S21 (RPS21), mRNA 4133 M00057252A:F06 MA193:F11 AF035555 gi|3116433|gb|AF035555.1AF035555 2.5E−182 Homo sapiens short chain L-3- hydroxyacyl-CoA dehydrogenase (SCHAD) mRNA, complete cds 4134 M00042573B:A02 MA167:B05 BC007583 gi|14043190|gb|BC007583.1BC007583 1.6E−102 Homo sapiens, clone MGC: 15572 IMAGE: 3140342, mRNA, complete cds 4135 M00042766A:E10 MA171:F05 AF201944 gi|9295191|gb|AF201944.1AF201944 2.8E−244 Homo sapiens HGTD-P (HGTD-P) mRNA, complete cds 4136 M00042882D:G08 MA167:A11 AF346964 gi|13272570|gb|AF346964.1AF346964 5.1E−199 Homo sapiens mitochondrion, complete genome 4137 M00042885C:A12 MA167:B11 NM_001018 gi|14591911|ref|NM_001018.2 Homo 1.9E−248 sapiens ribosomal protein S15 (RPS15), mRNA 4138 M00042815A:E07 MA171:B11 0.781 4139 M00042817B:E11 MA171:C11 AF077034 gi|4689115|gb|AF077034.1AF077034 5.6E−258 Homo sapiens HSPC010 mRNA, complete cds 4140 M00042887C:A07 MA167:E11 X73502 gi|406853|emb|X73502.1HSENCY20 H. Sapiens 2.1E−195 mRNA for cytokeratin 20 4141 M00042818D:A08 MA171:G11 NM_001002 gi|16933547|ref|NM_001002.2 Homo   2E−251 sapiens ribosomal protein, large, P0 (RPLP0), transcript variant 1, mRNA 4142 M00056552A:G08 MA174:C05 AK027892 gi|14042896|dbj|AK027892.1AK027892 2.4E−291 Homo sapiens cDNA FLJ14986 fis, clone Y79AA1000784, highly similar to Homo sapiens RanBP7/import 4143 M00056552C:D08 MA174:D05 BC017831 gi|17389602|gb|BC017831.1BC017831   2E−279 Homo sapiens, ribosomal protein L17, clone MGC: 22482 IMAGE: 4251433, mRNA, complete cds 4144 M00056553C:E10 MA174:E05 X14420 gi|30057|emb|X14420.1HSCOL3AI 5.8E−289 Human mRNA for pro-alpha-1 type 3 collagen 4145 M00056555B:C11 MA174:H05 M58458 gi|337509|gb|M58458.1HUMRPS4X 1.2E−196 Human ribosomal protein S4 (RPS4X) isoform mRNA, complete cds 4146 M00056611C:D03 MA174:D11 AF081192 gi|3420798|gb|AF081192.1AF081192 3.9E−293 Homo sapiens histone H2A.F/Z variant (H2AV) mRNA, complete cds 4147 M00056611D:B03 MA174:F11 L06498 gi|292442|gb|L06498.1HUMRPS20 Homo 3.E−169 sapiens ribosomal protein S20 (RPS20) mRNA, complete cds 4148 M00056611D:F08 MA174:G11 M19645 gi|183644|gb|M19645.1HUMGRP78 1.5E−289 Human 78 kdalton glucose-regulated protein (GRP78) gene, complete cds 4149 M00056614C:F06 MA174:H11 AB063318 gi|14517631|dbj|AB063318.1AB063318 5.7E−230 Homo sapiens MoDP-2, MoDP-3 mRNA for acute morphine dependence related protein 2, acute morphine 4150 RG:358387:10009:A05 MA158:A05 BC014270 gi|15679933|gb|BC014270.1BC014270 2.9E−266 Homo sapiens, protein kinase C, zeta, clone MGC: 10512 IMAGE: 3835020, mRNA, complete cds 4151 M00057302A:F08 MA182:A05 BC007097 gi|13937968|gb|BC007097.1BC007097 3.3E−147 Homo sapiens, tissue inhibitor of metalloproteinase 1 (erythroid potentiating activity, collagena 4152 M00057302C:H09 MA182:C05 BC018210 gi|17390469|gb|BC018210.1BC018210 2.1E−251 Homo sapiens, tubulin-specific chaperone a, clone MGC: 9129 IMAGE: 3861138, mRNA, complete cds 4153 M00054496A:B09 MA184:F05 0.60245 BC002589 gi|12803524|gb|BC002589.1BC002589 3.5E−64 Homo sapiens, proteasome (prosome, macropain) 26S subunit, ATPase, 2, clone MGC: 3004 IMAGE: 316179 4154 M00054496A:H05 MA184:H05 BC004138 gi|13278716|gb|BC004138.1BC004138 1.4E−286 Homo sapiens, ribosomal protein L6, clone MGC: 1635 IMAGE: 2823733, mRNA, complete cds 4155 M00042460B:A08 MA182:A11 NM_000980 gi|15431299|ref|NM_000980.2 Homo 8.7E−229 sapiens ribosomal protein L18a (RPL18A), mRNA 4156 M00054524B:B09 MA184:A11 NM_000976 gi|15431291|ref|NM_000976.2 Homo 4.1E−296 sapiens ribosomal protein L12 (RPL12), mRNA 4157 M00054526C:E05 MA184:B11 NM_000988 gi|17017972|ref|NM_000988.2 Homo   7E−189 sapiens ribosomal protein L27 (RPL27), mRNA 4158 M00042516B:A08 MA182:C11 NM_000976 gi|15431291|ref|NM_000976.2 Homo   2E−248 sapiens ribosomal protein L12 (RPL12), mRNA 4159 M00042517D:H10 MA182:D11 BC000386 gi|12653234|gb|BC000386.1BC000386 3.8E−178 Homo sapiens, eukaryotic translation initiation factor 3, subunit 3 (gamma, 40 kD), clone MGC: 8431 4160 M00054527B:H11 MA184:D11 AF155235 gi|6318598|gb|AF155235.1AF155235 4.5E−240 Homo sapiens 15.5 kD RNA binding protein mRNA, complete cds 4161 M00042517D:H11 MA182:E11 BC016756 gi|16876963|gb|BC016756.1BC016756 1.4E−230 Homo sapiens, glutathione peroxidase 2 (gastrointestinal), clone IMAGE: 3681457, mRNA 4162 M00054529C:G04 MA184:G11 NM_022551 gi|14165467|ref|NM_022551.2 Homo 2.7E−213 sapiens ribosomal protein S18 (RPS18), mRNA 4163 M00043300D:A06 MA182:H11 BC012146 gi|15082460|gb|BC012146.1BC012146 3.6E−259 Homo sapiens, Similar to ribosomal protein L3, clone MGC: 20359 IMAGE: 4549682, mRNA, complete cds 4164 M00054958A:G10 MA198:C05 AY007723 gi|15431041|gb|AY007723.1 Homo 2.6E−185 sapiens MAL2 proteolipid (MAL2) mRNA, complete cds 4165 M00054958B:B07 MA198:D05 0.12023 AF012108 gi|2331249|gb|AF012108.1AF012108 2.6E−111 Homo sapiens Amplified in Breast Cancer (AIB1) mRNA, complete cds 4166 M00054961D:E08 MA198:H05 NM_005617 gi|14141191|ref|NM_005617.2 Homo 3.2E−172 sapiens ribosomal protein S14 (RPS14), mRNA 4167 M00055015C:H02 MA198:C11 X58965 gi|35069|X58965.1HSNM23H2G 4.4E−187 H. sapiens RNA for nm23-H2 gene 4168 M00055016B:D03 MA198:E11 NM_001010 gi|17158043|ref|NM_001010.2 Homo 1.7E−186 sapiens ribosomal protein S6 (RPS6), mRNA 4169 M00055764D:D05 MA170:E05 BC001708 gi|12804576|gb|BC001708.1BC001708 9.8E−210 Homo sapiens, ribosomal protein S3A, clone MGC: 1626 IMAGE: 3544072, mRNA, complete cds 4170 M00055815C:E08 MA170:B11 AK025459 gi|10437979|dbj|AK025459.1AK025459 4.8E−249 Homo sapiens cDNA: FLJ21806 fis, clone HEP00829, highly similar to HSTRA1 Human tra1 mRNA for hu 4171 M00055819B:B12 MA170:F11 AF014838 gi|2281706|gb|AF014838.1AF014838 8.3E−254 Homo sapiens galectin-4 mRNA, complete cds 4172 M00055820C:H11 MA170:H11 NM_000967 gi|16507968|ref|NM_000967.2 Homo 3.4E−175 sapiens ribosomal protein L3 (RPL3), mRNA 4173 M00055204B:C04 MA196:A05 X57351 gi|311373|emb|X57351.1HS18D Human 1- 1.2E−218 8D gene from interferon-inducible gene family 4174 M00055209A:C09 MA196:D05 AF028832 gi|3287488|gb|AF028832.1AF028832 9.1E−232 Homo sapiens Hsp89-alpha-delta-N mRNA, complete cds 4175 M00055252C:G12 MA196:D11 0.1038 U16738 gi|608516|gb|U16738.1HSU16738 Homo   1E−172 sapiens CAG-isl 7 mRNA, complete cds 4176 M00056934C:D08 MA177:A05 Z69043 gi|2398656|emb|Z69043.1HSTRAPRNA 3.2E−281 H. sapiens mRNA translocon-associated protein delta subunit precursor 4177 M00055989C:D03 MA179:B05 0.8 4178 M00056937C:G12 MA177:D05 AK055020 gi|16549662|dbj|AK055020.1AK055020 3.2E−219 Homo sapiens cDNA FLJ30458 fis, clone BRACE2009421, highly similar to NUCLEOSOME ASSEMBLY PROTEI 4179 M00055997B:A02 MA179:H05 0.89264 4180 M00056087A:G01 MA179:C11 AF150754 gi|12484558|gb|AF150754.2AF150754 2.4E−96 Homo sapiens 3′phosphoadenosine 5′- phosphosulfate synthase 2b isoform mRNA, complete cds 4181 M00056091A:H05 MA179:D11 BC013724 gi|15489238|gb|BC013724.1BC013724 3.9E−265 Homo sapiens, ferritin, heavy polypeptide 1, clone MGC: 17255 IMAGE: 3857790, mRNA, complete cds 4182 M00056966B:A05 MA177:E11 AF346974 gi|13272710|gb|AF346974.1AF346974 5.6E−108 Homo sapiens mitochondrion, complete genome 4183 M00056093A:F08 MA179:F11 0.26754 4184 M00056096C:H10 MA179:H11 0.77419 4185 M00054766B:E10 MA188:H05 BC005328 gi|13529103|gb|BC005328.1BC005328 5.8E−258 Homo sapiens, ribosomal protein S27a, clone MGC: 12414, mRNA, complete cds 4186 M00054817B:H09 MA188:B11 BC015465 gi|15930040|gb|BC015465.1BC015465 8.4E−254 Homo sapiens, HSPC023 protein, clone MGC: 8754 IMAGE: 3914049, mRNA, complete cds 4187 M00054818D:G04 MA188:D11 BC008495 gi|14250151|gb|BC008495.1BC008495 1.4E−258 Homo sapiens, nucleophosmin (nucleolar phosphoprotein B23, numatrin), clone MGC: 14826 IMAGE: 42766 4188 M00042851D:H04 MA172:A05 NM_001000 gi|16306563|ref|NM_001000.2 Homo 3.7E−156 sapiens ribosomal protein L39 (RPL39), mRNA 4189 M00042853A:F01 MA172:B05 NM_000970 gi|16753226|ref|NM_000970.2 Homo 3.4E−284 sapiens ribosomal protein L6 (RPL6), mRNA 4190 M00055426A:G06 MA168:E05 AF272149 gi|9971873|gb|AF272149.1AF272149 1.3E−61 Homo sapiens hepatocellular carcinoma associated-gene TB6, mRNA sequence 4191 M00055496A:G12 MA168:B11 AF203815 gi|6979641|gb|AF203815.1AF203815 5.6E−202 Homo sapiens alpha gene sequence 4192 M00055509C:C02 MA168:F11 0.76684 AL590401 gi|14422235|emb|AL590401.6AL590401 1.8E−35 Human DNA sequence from clone RP11- 466P12 on chromosome 6, complete sequence [Homo sapiens] 4193 M00055510B:F08 MA168:G11 AF067174 gi|4894381|gb|AF067174.1AF067174 2.2E−257 Homo sapiens retinol dehydrogenase homolog mRNA, complete cds 4194 M00055510D:A08 MA168:H11 AK026649 gi|10439547|dbj|AK026649.1AK026649 1.6E−161 Homo sapiens cDNA: FLJ22996 fis, clone KAT11938 4195 M00056748C:B08 MA175:B05 AF054183 gi|4092053|gb|AF054183.1AF054183 1.2E−165 Homo sapiens GTP binding protein mRNA, complete cds 4196 M00056749A:F01 MA175:C05 Y14736 gi|2765422|emb|Y14736.1HSIGG1KL 1.2E−249 Homo sapiens mRNA for immunoglobulin kappa light chain 4197 M00056754B:A10 MA175:G05 V00710 gi|13683|emb|V00710.1MIT1HS Human 6.3E−292 mitochondrial genes for several tRNAs (Phe, Val, Leu) and 12S and 16S ribosomal RNAs 4198 M00056754B:H06 MA175:H05 D38112 gi|644480|dbj|D38112.1HUMMTA Homo 1.4E−252 sapiens mitochondrial DNA, complete sequence 4199 RG:1653390:10014:E05 MA163:E05 M15353 gi|306486|gb|M15353.1HUMIF4E Homo 1.5E−138 sapiens cap-binding protein mRNA, complete cds 4200 RG:1669553:10014:G05 MA163:G05 X03663 gi|29899|emb|X03663.1HSCFMS Human 5.8E−221 mRNA for c-fms proto-oncogene 4201 M00043355A:H12 MA183:B05 M94314 gi|292436|gb|M94314.1HUMRPL30A 7.9E−66 Homo sapiens ribosomal protein L30 mRNA, complete cds 4202 M00043355B:F10 MA183:C05 AK055653 gi|16550433|dbj|AK055653, 1AK055653 1.1E−165 Homo sapiens cDNA FLJ31091 fis, clone IMR321000155, highly similar to 60S RIBOSOMAL PROTEIN L35A 4203 M00043357B:B10 MA183:G05 NM_000978 gi|14591907|ref|NM_000978.2 Homo 3.7E−206 sapiens ribosomal protein L23 (RPL23), mRNA 4204 M00054557C:D09 MA185:G05 NM_012423 gi|14591905|ref|NM_012423.2 Homo 9.6E−167 sapiens ribosomal protein L13a (RPL13A), mRNA 4205 M00043358B:G11 MA183:H05 M60854 gi|338446|gb|M60854.1HUMSRAA 5.2E−280 Human ribosomal protein S16 mRNA, complete cds 4206 M00043396D:B04 MA183:A11 AF026166 gi|4090928|gb|AF026166.1AF026166 4.1E−237 Homo sapiens chaperonin-containing TCP- 1 beta subunit homolog mRNA, complete cds 4207 M00054612D:D11 MA185:H11 NM_006013 gi|15718685|ref|NM_006013.2 Homo 1.2E−171 sapiens ribosomal protein L10 (RPL10), mRNA 4208 M00055409B:D08 MA199:A05 BC016748 gi|16876941|gb|BC016748.1BC016748 3.6E−55 Homo sapiens, ribosomal protein L37a, clone MGC: 26772 IMAGE: 4831278, mRNA, complete cds 4209 M00055409D:F06 MA199:B05 V00572 gi|35434|emb|V00572.1HSPGK1 Human 1.6E−186 mRNA encoding phosphoglycerate kinase 4210 M00055410A:A06 MA199:C05 0.80422 4211 M00056659A:D08 MA186:F05 M15470 gi|187680|gb|M15470.1HUMMHB44   3E−275 Human MHC class I HLA-B44 mRNA, partial cds 4212 M00056704C:H08 MA186:D11 BC001125 gi|12654578|gb|BC001125.1BC001125 8.2E−282 Homo sapiens, peptidylprolyl isomerase B (cyclophilin B), clone MGC: 2224 IMAGE:2966791, mRNA, com 4213 M00055553C:B06 MA169:A06 4214 M00056280B:D10 MA181:A06 0.72079 4215 M00056282D:G10 MA181:C06 0.05211 AJ420520 gi|17066384|emb|AJ420520.1HSA420520 1.5E−88 Homo sapiens mRNA full length insert cDNA clone EUROIMAGE 1979495 4216 M00056288B:A12 MA181:G06 D14530 gi|414348|dbj|D14530.1HUMRSPT 9.8E−23 Human homolog of yeast ribosomal protein S28, complete cds 4217 M00055686D:E11 MA169:B12 L02785 gi|291963|gb|L02785.1HUMDRA Homo 5.9E−202 sapiens colon mucosa-associated (DRA) mRNA, complete cds 4218 M00042346B:F09 MA181:C12 0.23093 AK000168 gi|7020079|dbj|AK000168.1AK000168 7.4E−202 Homo sapiens cDNA FLJ20161 fis, clone COL09252, highly similar to L33930 Homo sapiens CD24 signal 4219 M00055698C:E05 MA169:E12 0.82609 4220 M00042347C:D07 MA181:E12 M12759 gi|532596|gb|M12759.1HUMIGJ02 3.2E−166 Human Ig J chain gene, exons 3 and 4 4221 M00055702C:C04 MA169:F12 0.85 4222 M00042348C:F03 MA181:G12 x60489 gi|31099|emb|X60489.1HSEF1B Human 6.68E−233 mRNA for elongation factor-1-beta 4223 M00055335D:E01 MA197:D06 BC003510 gi|13097578|gb|BC003510.1BC003510 2.6E−176 Homo sapiens, prothymosin, alpha (gene sequence 28), clone MGC: 10549 IMAGE: 3610808, mRNA, complet 4224 M00056180C:E06 MA180:B06 BC018190 gi|17390422|gb|BC018190.1BC018190 5.3E−171 Homo sapiens, Similar to metallothionein 1L, clone MGC: 9187 IMAGE: 3859643, mRNA, complete cds 4225 M00056184B:G11 MA180:D06 Y00345 gi|35569|emb|Y00345.1HSPOLYAB 8.2E−254 Human mRNA for polyA binding protein 4226 M00056514A:F06 MA173:A12 AJ335311 gi|15879729|emb|AJ335311.1HSA335311 7.7E−54 Homo sapiens genomic sequence surrounding NotI site, clone NR1-WB8C 4227 M00056514C:H11 MA173:D12 BC000386 gi|12653234|gb|BC000386.1BC000386 1.8E−242 Homo sapiens, eukaryotic translation initiation factor 3, subunit 3 (gamma, 40 kD), clone MGC: 8431 4228 M00054674D:C05 MA187:C06 D14530 gi|414348|dbj|D14530.1HUMRSPT 8.3E−198 Human homolog of yeast ribosomal protein S28, complete cds 4229 M00054675A:H07 MA187:D06 X00474 gi|35706|emb|X00474.1HSPS2 Human pS2 7.8E−170 mRNA induced by estrogen from human breast cancer cell line MCF-7 4230 M00054878A:G12 MA189:D06 AL359678 gi|15215911|emb|AL359678.15AL359678 2.4E−207 Human DNA sequence from clone RP11- 550J21 on chromosome 9, complete sequence [Homo sapiens] 4231 M00054676B:D07 MA187:H06 BC000749 gi|13879207|gb|BC000749.1BC000749 2.9E−129 Homo sapiens, lactate dehydrogenase A, clone MGC: 2417 IMAGE: 2960999, mRNA, complete cds 4232 M00054725A:E09 MA187:B12 NM_022551 gi|14165467|ref|NM_022551.2 Homo 2.7E−241 sapiens ribosomal protein S18 (RPS18), mRNA 4233 M00054924C:B09 MA189:C12 0.63711 4234 M00054726D:B04 MA187:D12 X16064 gi|37495|emb|X16064.1HSTUMP Human 1.1E−271 mRNA for translationally controlled tumor protein 4235 M00054927A:H09 MA189:E12 X06705 gi|35511|emb|X06705.1HSPLAX Human 2.7E−297 PLA-X mRNA 4236 M00054727C:F11 MA187:F12 0.7234 4237 M00054728A:H05 MA187:H12 X16064 gi|37495|emb|X16064.1HSTUMP Human 1.3E−168 mRNA for translationally controlled tumor protein 4238 M00054930B:G05 MA189:H12 U15008 gi|600747|gb|U15008.1HSU15008 Human   7E−270 SnRNP core protein Sm D2 mRNA, complete cds 4239 M00057214C:G11 MA193:B06 U55206 gi|2957143|gb|U55206.1HSU55206 Homo 4.1E−115 sapiens human gamma-glutamyl hydrolase (hGH) mRNA, complete cds 4240 M00057216C:G01 MA193:D06 BC000695 gi|12653812|gb|BC000695.1BC000695 7.3E−28 Homo sapiens, Similar to tetraspan 1, clone IMAGE: 3349380, mRNA 4241 M00057217C:B07 MA193:F06 AK057120 gi|16552707|dbj|AK057120.1AK057120 3.6E−206 Homo sapiens cDNA FLJ32558 fis, clone SPLEN1000143, highly similar to HIGH MOBILITY GROUP PROTEL 4242 M00042695A:H04 MA167:B06 BC007075 gi|13937928|gb|BC007075.1BC007075 9.6E−37 Homo sapiens, hemoglobin, beta, clone MGC: 14540 IMAGE: 4292125, mRNA, complete cds 4243 M00042695D:D09 MA167:C06 BC018749 gi|17511797|gb|BC018749.1BC018749 3.5E−194 Homo sapiens, Similar to immunoglobulin lambda joining 3, clone MGC: 31942 IMAGE: 4854511, mRNA, co 4244 M00042771A:D01 MA171:D06 BC007659 gi|4043327|gb|BC007659.1BC007659 6.7E−239 Homo sapiens, diaphorase (NADH/NADPH) (cytochrome b-5 reductase), clone MGC: 2073 IMAGE: 3349257, m 4245 M00042772D:F02 MA171:E06 NM_002295 gi|9845501|ref|NM_002295.2 Homo 2.2E−254 sapiens laminin receptor 1 (67 kD, ribosomal protein SA) (LAMR1), mRNA 4246 M00042773A:A12 MA171:F06 AK000009 gi|7019813|dbj|AK000009.1AK000009 2.6E−213 Homo sapiens cDNA FLJ20002 fis, clone ADKA01577 4247 M00042699B:B10 MA167:G06 X98311 gi|1524059|emb|X98311.1HSCGM2ANT 1.5E−31 H. sapiens mRNA for carcinoembryonic antigen family member 2, CGM2 4248 M00042889A:H07 MA167:A12 NM_005950 gi|10835229|ref|NM_005950.1 Homo   6E−202 sapiens metallothionein 1G (MT1G), mRNA 4249 M00042819A:C09 MA171:A12 BC009220 gi|14327996|gb|BC009220.1BC009220 5.2E−218 Homo sapiens, clone MGC: 16362 IMAGE: 3927795, mRNA, complete cds 4250 M00042819C:B03 MA171:B12 NM_000995 gi|16117786|ref|NM_000995.2 Homo 9.4E−207 sapiens ribosomal protein L34 (RPL34), transcript variant 1, mRNA 4251 M00042895B:C02 MA167:C12 AF217186 gi|11526786|gb|AF217186.1AF217186 1.4E−283 Homo sapiens inorganic pyrophosphatase 1 (PPA1) mRNA, complete cds 4252 M00042823B:A02 MA171:C12 A1F212248 gi|13182770|gb|AF212248.1AF212248 5.1E−252 Homo sapiens CDA09 mRNA, complete cds 4253 M00042895D:B04 MA167:E12 U83908 gi|1825561|gb|U83908.1HSU83908 2.4E−229 Human nuclear antigen H731 mRNA, complete cds 4254 M00056564B:F11 MA174:F06 AL136593 gi|7018431|emb|AL136593.1HSM801567 3.4E−284 Homo sapiens mRNA; cDNA DKFZp761K102 (from clone DKFZp761K102); complete cds 4255 M00056564C:E08 MA174:G06 Z74616 gi|1418929|emb|Z74616.1HSPPA2ICO 1.4E−286 H. sapiens mRNA for prepro-alpha2(I) collagen 4256 M00056615D:A01 MA174:A12 X12881 gi|34036|emb|X12881.1HSKER18R 1.8E−273 Human mRNA for cytokeratin 18 4257 M00056620D:F02 MA174:G12 AK000335 gi|7020350|dbj|AK000335.1AK000335 3.5E−287 Homo sapiens cDNA FLJ20328 fis, clone HEP10039 4258 RG:359184:10009:A06 MA158:A06 M35663 gi|189505|gb|M35663.1HUMP68A Human 1.6E−258 p68 kinase mRNA, complete cds 4259 RG:428530:10009:D12 MA158:D12 AF321918 gi|12958659|gb|AF321918.1AF321918 0 Homo sapiens testicular acid phosphatase (ACPT) gene, complete cds, alternatively spliced product 4260 M00057310A:A07 MA182:A06 AF054187 gi|4092059|gb|AF054187.1AF054187 7.3E−143 Homo sapiens alpha NAC mRNA, complete cds 4261 M00054503C:H10 MA184:F06 BC018828 gi|17402971|gb|BC018828.1BC018828   2E−276 Homo sapiens, clone IMAGE: 3343539, mRNA 4262 M00043302C:D03 MA182:C12 BC006791 gi|13905015|gb|BC006791.1BC006791 8.3E−282 Homo sapiens, ribosomal protein L10a, clone MGC: 5203 IMAGE: 2901249, mRNA, complete cds 4263 M00054535B:F10 MA184:F12 S35960 gi|249370|gb|S35960.1S35960 laminin 4.1E−112 receptor homolog {3′ region} [human, mRNA Partial, 739 nt] 4264 M00054535C:D10 MA184:G12 BC008063 gi|14165520|gb|BC008063.1BC008063 4.7E−274 Homo sapiens, Similar to KIAA0102 gene product, clone MGC: 2249 IMAGE: 2967488, mRNA, complete cds 4265 M00054535C:H09 MA184:H12 AB020680 gi|4240234|dbj|AB020680.1AB020680 3.1E−275 Homo sapiens mRNA for KIAA0873 protein, partial cds 4266 M00054964B:A08 MA198:C06 BC017189 gi|16877928|gb|BC017189.1BC017189 1.1E−190 Homo sapiens, myo-iositol 1-phosphate synthase A1, clone MGC: 726 IMAGE: 3140452, mRNA, complete c 4267 M00054966C:H01 MA198:D06 BC018828 gi|17402971|gb|BC018828.1BC018828 4.4E−190 Homo sapiens, clone IMAGE: 3343539, mRNA 4268 M00055022D:F01 MA198:D12 NM_000975 gi|15431289|ref|NM_000975.2 Homo 2.5E−182 sapiens ribosomal protein L11 (RPL11), mRNA 4269 M00055026C:C12 MA198:G12 NM_007209 gi|16117792|ref|NM_007209.2 Homo   4E−184 sapiens ribosomal protein L35 (RPL35), mRNA 4270 M00055027B:C11 MA198:H12 AF283772 gi|10281741|gb|AF283772.2AF283772   1E−187 Homo sapiens clone TCBAP0781 mRNA sequence 4271 M00055826D:C11 MA170:E12 0.7443 4272 M00055828C:D10 MA170:G12 V00662 gi|13003|emb|V00662.1MIHSXX 9.5E−229 H. sapiens mitochondrial genome 4273 M00055828D:F12 MA170:H12 0.71968 BC001573 gi|16306770|gb|BC001573.1BC001573 2.8E−37 Homo sapiens, clone MGC: 5522 IMAGE: 3454199, mRNA, complete cds 4274 M00055215C:E11 MA196:B06 BC001118 gi|12654566|gb|BC001118.1BC001118 2.4E−288 Homo sapiens, Similar to seven transmembrane domain protein, clone MGC: 1936 IMAGE: 2989840, mRNA, 4275 M00055217C:E09 MA196:D06 BC010187 gi|14603477|gb|BC010187.1BC010187 4.3E−215 Homo sapiens, ribosomal protein S11, clone MGC: 20218 IMAGE: 4547934, mRNA, complete cds 4276 M00055221B:C01 MA196:E06 NM_001016 gi|14277699|ref|NM_001016.2 Homo 4.7E−246 sapiens ribosomal protein S12 (RPS12), mRNA 4277 M00055222A:E02 MA196:G06 NM_000987 gi|17017970|ref|NM_000987.2 Homo 2.1E−226 sapiens ribosomal protein L26 (RPL26), mRNA 4278 M00056226D:F03 MA180:B12 BC011835 gi|15080118|gb|BC011835.1BC011835 1.7E−57 Homo sapiens, Similar to ATPase, Na+/K+ transporting, beta 3 polypeptide, clone MGC: 20152 IMAGE: 3 4279 M00055258A:G02 MA196:F12 BC016753 gi|16876954|gb|BC016753.1BC016753 1.3E−102 Homo sapiens, clone MGC: 1138 IMAGE: 2987963, mRNA, complete cds 4280 M00055998A:A02 MA179:A06 AF343729 gi|13649973|gb|AF343729.1AF343729 1.4E−283 Homo sapiens 3-alpha hydroxysteroid dehydrogenase mRNA, complete cds 4281 M00056945A:B11 MA177:A06 0.89778 4282 M00056945D:H03 MA177:C06 0.71282 4283 M00056001A:F11 MA179:D06 BC015983 gi|16359036|gb|BC015983.1BC015983 4.5E−165 Homo sapiens, clone IMAGE: 4074053, mRNA 4284 M00056946D:B04 MA177:F06 AF028832 gi|3287488|gb|AF028832.1AF028832   1E−296 Homo sapiens Hsp89-alpha-delta-N mRNA, complete cds 4285 M00056101B:B02 MA179:A12 AL049999 gi|4884252|emb|AL049999.1HSM800347   3E−100 Homo sapiens mRNA; cDNA DKFZp564M182 (from clone DKFZp564M182); partial cds 4286 M00056110C:D09 MA179:E12 AK024903 gi|10437317|dbj|AK024903.1AK024903   1E−209 Homo sapiens cDNA: FLJ21250 fis, clone COL01253, highly similar to AB020527 Homo sapiens mRNA fo 4287 M00056111B:H03 MA179:F12 0.81436 4288 M00054772B:H06 MA188:G06 L19185 gi|440307|gb|L19185.1HUMNKEFB 3.6E−178 Human natural killer cell enhancing factor (NKEFB) mRNA, complete cds 4289 M00054825B:B05 MA188:C12 0.09038 NM_005348 gi|13129149|ref|NM_005348.1 Homo 4.1E−222 sapiens heat shock 90 kD protein 1, alpha (HSPCA), mRNA 4290 M00054831A:G04 MA188:D12 AL359585 gi|8655645|emb|AL359585.1HSM802687 6.2E−116 Homo sapiens mRNA; cDNA DKFZp762B195 (from clone DKFZp762B195) 4291 M00054831D:B07 MA188:F12 U43701 gi|1399085|gb|U43701.1HSU43701 4.2E−296 Human ribosomal protein L23a mRNA, complete cds 4292 M00042862D:A12 MA172:B06 BC007097 gi|13937968|gb|BC007097.1BC007097 1.9E−248 Homo sapiens, tissue inhibitor of metalloproteinase 1 (erythroid potentiating activity, collagena 4293 M00042864A:E05 MA172:E06 0.59184 4294 M00042864D:E06 MA172:F06 NM_007099 gi|6005987|ref|NM_007099.1 Homo 3.5E−228 sapiens acid phosphatase 1, soluble (ACP1), transcript variant b, mRNA 4295 M00055514B:A05 MA168:E12 BC001190 gi|12654700|gb|BC001190.1BC001190 1.4E−230 Homo sapiens, Similar to creatine kinase, brain, clone MGC: 3160 IMAGE: 3354679, mRNA, complete cds 4296 M00056763B:A12 MA175:D06 NM_004417 gi|7108342|ref|NM_004417.2 Homo 6.4E−267 sapiens dual specificity phosphatase 1 (DUSP1), mRNA 4297 M00056767D:F06 MA175:F06 AF203815 gi|6979641|gb|AF203815.1AF203815 8.6E−285 Homo sapiens alpha gene sequence 4298 M00056821A:D08 MA175:A12 NM_001016 gi|14277699|ref|NM_001016.2 Homo 8.3E−220 sapiens ribosomal protein S12 (RPS12), mRNA 4299 M00056822C:G03 MA175:C12 NM_000970 gi|16753226|ref|NM_000970.2 Homo 3.4E−284 sapiens ribosomal protein L6 (RPL6), mRNA 4300 M00056823D:H02 MA175:E12 BC018828 gi|17402971|gb|BC018828.1BC018828 1.9E−276 Homo sapiens, clone IMAGE: 3343539, mRNA 4301 RG:1609994:10014:A06 MA163:A06 BC006322 gi|13623444|gb|BC006322.1BC006322   1E−300 Homo sapiens, activating transcription factor 3, clone MGC: 12746 IMAGE: 4138076, mRNA, complete cd 4302 RG:1667183:10014:F12 MA163:F12 BC000013 gi|12652546|gb|BC000013.1BC000013 5.4E−58 Homo sapiens, insulin-like growth factor binding protein 3, clone MGC: 2305 IMAGE: 3506666, mRNA, c 4303 M00043358D:C06 MA183:A06 AF113008 gi|6642739|gb|AF113008.1AF113008 1.5E−152 Homo sapiens clone FLB0708 mRNA sequence 4304 M00054558B:E05 MA185:A06 0.69811 BC014498 gi|15680272|gb|BC014498.1BC014498 1.1E−27 Homo sapiens, clone IMAGE: 4856273, mRNA 4305 M00043361B:G03 MA183:E06 NM_001025 gi|14790142|ref|NM_001025.2 Homo 1.3E−218 sapiens ribosomal protein S23 (RPS23), mRNA 4306 M00043408C:D11 MA183:G12 U14967 gi|550014|gb|U14967.1HSU14967 Human 1.4E−283 ribosomal protein L21 mRNA, complete cds 4307 M00054632A:E11 MA185:H12 0.18764 X73459 gi|313660|emb|X73459.1HSSRP14A   2E−140 H. sapiens mRNA for signal recognition particle subunit 14 4308 M00056661A:G05 MA186:A06 L18960 gi|306724|gb|L18960.1HUMEIF4C Human 5.2E−280 protein synthesis factor (eIF-4C) mRNA, complete cds 4309 M00056661C:C11 MA186:B06 S72481 gi|632789|gb|S72481.1S72481 pantophysin 3.4E−281 [human, keratinocyte line HaCaT, mRNA, 2106 nt] 4310 M00055412D:E05 MA199:B06 M26697 gi|189311|gb|M26697.1HUMNUMB23 8.9E−176 Human nucleolar protein (B23) mRNA, complete cds 4311 M00055413A:G12 MA199:C06 BC012354 gi|15214456|gb|BC012354.1BC012354 1.9E−95 Homo sapiens, clone MGC: 20390 IMAGE: 4564801, mRNA, complete cds 4312 M00055414D:A09 MA199:D06 X06705 gi|35511|emb|X06705.1HSPLAX Human 4.1E−187 PLA-X mRNA 4313 M00056707B:C01 MA186:C12 AF178581 gi|10800410|gb|AF178581.2AF178581 1.3E−252 Homo sapiens nasopharyngeal carcinoma gene sequence 4314 M00056237D:C10 MA181:D01 0.64821 4315 M00056238B:D03 MA181:E01 AF083241 gi|5106776|gb|AF083241.1HSPC024 9.4E−257 Homo sapiens HSPC024 mRNA, complete cds 4316 M00056239B:D05 MA181:G01 0.89873 4317 M00056241B:H07 MA181:H01 0.625 NM_033340 gi|1571870|ref|NM_033340.1 Homo 2.2E−50 sapiens caspase 7, apoptosis-related cysteine protease (CASP7), transcript variant beta, mRNA 4318 1:2921194:04B02:C06 MA118:C06 AB006780 gi|2385451|dbj|AB006780.1AB006780 3.1E−222 Homo sapiens mRNA for galectin-3, complete cds 4319 I:1624865:04B02:G06 MA118:G06 U15009 gi|600749|gb|U15009.1HSU15009 Human 4.7E−246 SnRNP core protein Sm D3 mRNA, complete cds 4320 I:1728607:04A02:H06 MA116:H06 BC016164 gi|16740573|gb|BC016164.1BC016164 IE−262 Homo sapiens, small inducible cytokine subfamily D (Cys-X3-Cys), member 1 (fractalkine, neurotact 4321 I:2827453:04B02:H06 MA118:H06 U27143 gi|862932|gb|U27143.1HSU27143 Human 2.5E−113 protein kinase C inhibitor-I cDNA, complete cds 4322 I:2070593:04B02:D12 MA118:D12 D83004 gi|1181557|dbj|D83004.1D83004 Human 1.5E−233 epidennoid carcinoma mRNA for ubiquitin-conjugating enzyme E2 similar to Drosophila bendless ge 4323 I:2683114:04A02:H12 MA116:H12 L20493 gi|306754|gb|L20493.1HUMGAGLUTD   1E−300 Human gamma-glutamyl transpeptidase mRNA, complete cds 4324 I:1809336:02A02:G06 MA108:G06 U09117 gi|483919|gb|U09117.1HSU09117 Human 1.3E−280 phospholipase c delta 1 mRNA, complete cds

Example 50 Detection of Differential Expression Using Arrays

cDNA probes were prepared from total RNA isolated from the patient cells described above. Since LCM provides for the isolation of specific cell types to provide a substantially homogenous cell sample, this provided for a similarly pure RNA sample.

Total RNA was first reverse transcribed into cDNA using a primer containing a T7 RNA polymerase promoter, followed by second strand DNA synthesis. cDNA was then transcribed in vitro to produce antisense RNA using the T7 promoter-mediated expression (see, e.g., Luo et al. (1999) Nature Med 5:117-122), and the antisense RNA was then converted into cDNA. The second set of cDNAs were again transcribed in vitro, using the T7 promoter, to provide antisense RNA. Optionally, the RNA was again converted into cDNA, allowing for up to a third round of T7-mediated amplification to produce more antisense RNA. Thus the procedure provided for two or three rounds of in vitro transcription to produce the final RNA used for fluorescent labeling.

Fluorescent probes were generated by first adding control RNA to the antisense RNA mix, and producing fluorescently labeled cDNA from the RNA starting material. Fluorescently labeled cDNAs prepared from the tumor RNA sample were compared to fluorescently labeled cDNAs prepared from normal cell RNA sample. For example, the cDNA probes from the normal cells were labeled with Cy3 fluorescent dye (green) and the cDNA probes prepared from the tumor cells were labeled with Cy5 fluorescent dye (red), and vice versa.

Each array used had an identical spatial layout and control spot set. Each microarray was divided into two areas, each area having an array with, on each half, twelve groupings of 32×12 spots, for a total of about 9,216 spots on each array. The two areas are spotted identically which provide for at least two duplicates of each clone per array.

Polynucleotides for use on the arrays were obtained from both publicly available sources and from cDNA libraries generated from selected cell lines and patient tissues as described above and in Table 29. PCR products of from about 0.5 kb to 2.0 kb amplified from these sources were spotted onto the array using a Molecular Dynamics Gen III spotter according to the manufacturer's recommendations. The first row of each of the 24 regions on the array had about 32 control spots, including 4 negative control spots and 8 test polynucleotides. The test polynucleotides were spiked into each sample before the labeling reaction with a range of concentrations from 2-600 pg/slide and ratios of 1:1. For each array design, two slides were hybridized with the test samples reverse-labeled in the labeling reaction. This provided for about four duplicate measurements for each clone, two of one color and two of the other, for each sample.

The differential expression assay was performed by mixing equal amounts of probes from tumor cells and normal cells of the same patient. The arrays were prehybridized by incubation for about 2 hrs at 60° C. in 5×SSC/0.2% SDS/1 mM EDTA, and then washed three times in water and twice in isopropanol. Following prehybridization of the array, the probe mixture was then hybridized to the array under conditions of high stringency (overnight at 42° C. in 50% formamide, 5×SSC, and 0.2% SDS. After hybridization, the array was washed at 55° C. three times as follows: 1) first wash in 1×SSC/0.2% SDS; 2) second wash in 0.1×SSC/0.2% SDS; and 3) third wash in 0.1×SSC.

The arrays were then scanned for green and red fluorescence using a Molecular Dynamics Generation III dual color laser-scanner/detector. The images were processed using BioDiscovery Autogene software, and the data from each scan set normalized to provide for a ratio of expression relative to normal. Data from the microarray experiments was analyzed according to the algorithms described in U.S. application Ser. No. 60/252,358, filed Nov. 20, 2000, by E. J. Moler, M. A. Boyle, and F. M. Randazzo, and entitled “Precision and accuracy in cDNA microarray data,” which application is specifically incorporated herein by reference.

The experiment was repeated, this time labeling the two probes with the opposite color in order to perform the assay in both “color directions.” Each experiment was sometimes repeated with two more slides (one in each color direction). The level fluorescence for each sequence on the array expressed as a ratio of the geometric mean of 8 replicate spots/genes from the four arrays or 4 replicate spots/gene from 2 arrays or some other permutation. The data were normalized using the spiked positive controls present in each duplicated area, and the precision of this normalization was included in the final determination of the significance of each differential. The fluorescent intensity of each spot was also compared to the negative controls in each duplicated area to determine which spots have detected significant expression levels in each sample.

A statistical analysis of the fluorescent intensities was applied to each set of duplicate spots to assess the precision and significance of each differential measurement, resulting in a p-value testing the null hypothesis that there is no differential in the expression level between the tumor and normal samples of each patient. During initial analysis of the microarrays, the hypothesis was accepted if p>1 , and the differential ratio was set to 1.000 for those spots. All other spots have a significant difference in expression between the tumor and normal sample. If the tumor sample has detectable expression and the normal does not, the ratio is truncated at 1000 since the value for expression in the normal sample would be zero, and the ratio would not be a mathematically useful value (e.g., infinity). If the normal sample has detectable expression and the tumor does not, the ratio is truncated to 0.001, since the value for expression in the tumor sample would be zero and the ratio would not be a mathematically useful value. These latter two situations are referred to herein as “on/off.” Database tables were populated using a 95% confidence level (p>0.05).

Table 31 provides the results for gene products that were expressed by at least 2-fold or greater in the colon tumor samples relative to normal tissue samples in at least 20% of the patients tested, or gene products in which expression levels of the gene in colon tumor cells was less than or equal to ½ of the expression level in normal tissue samples in at least 20% of the patients tested. Table 31 includes: (1) the “SEQ ID NO” of the sequence tested; (2) the spot identification number (“Spot ID”); (3) the “Clone ID” assigned to the clone from which the sequence was isolated; (4) the “MAClone ID” assigned to the clone from which the sequence was isolated; (5) the percentage of patients tested in which expression levels (e.g., as message level) of the gene was at least 2-fold greater in cancerous tissue than in matched normal tissue (“>=2×”); (6) the percentage of patients tested in which expression levels (e.g., as message level) of the gene was at least 5-fold greater in cancerous tissue than in matched normal tissue (“>=5×”); (7) the percentage of patients tested in which expression levels (e.g., as message level) of the gene was less than or equal to ½ of the expression level in matched normal cells (“<=half×”); and (8) the number of patients analyzed (“Num Ratios”).

Table 31 also includes the results from each patient, identified by the patient ID number (e.g., 10). This data represents the ratio of differential expression for the samples tested from that particular patient's tissues (e.g., “10” is the ratio from the tissue samples of Patient ID no. 10). The ratios of differential expression are expressed as a normalized hybridization signal associated with the tumor probe divided by the normalized hybridization signal with the normal probe. Thus, a ratio greater than 1 indicates that the gene product is increased in expression in cancerous cells relative to normal cells, while a ratio of less than 1 indicates the opposite.

These data provide evidence that the genes represented by the polynucleotides having the indicated sequences are differentially expressed in colon cancer as compared to normal non-cancerous colon tissue.

Example 51 Antisense Regulation of Gene Expression

The expression of the differentially expressed genes represented by the polynucleotides in the cancerous cells can be analyzed using antisense knockout technology to confirm the role and function of the gene product in tumorigenesis, e.g., in promoting a metastatic phenotype.

A number of different oligonucleotides complementary to the mRNA generated by the differentially expressed genes identified herein can be designed as potential antisense oligonucleotides, and tested for their ability to suppress expression of the genes. Sets of antisense oligomers specific to each candidate target are designed using the sequences of the polynucleotides corresponding to a differentially expressed gene and the software program HYBsimulator Version 4 (available for Windows 95/Windows NT or for Power Macintosh, RNAture, Inc. 1003 Health Sciences Road, West, Irvine, Calif. 92612 USA). Factors that are considered when designing antisense oligonucleotides include: 1) the secondary structure of oligonucleotides; 2) the secondary structure of the target gene; 3) the specificity with no or minimum cross-hybridization to other expressed genes; 4) stability; 5) length and 6) terminal GC content. The antisense oligonucleotide is designed so that it will hybridize to its target sequence under conditions of high stringency at physiological temperatures (e.g., an optimal temperature for the cells in culture to provide for hybridization in the cell, e.g., about 37° C.), but with minimal formation of homodimers.

Using the sets of oligomers and the HYBsimulator program, three to ten antisense oligonucleotides and their reverse controls are designed and synthesized for each candidate mRNA transcript, which transcript is obtained from the gene corresponding to the target polynucleotide sequence of interest. Once synthesized and quantitated, the oligomers are screened for efficiency of a transcript knock-out in a panel of cancer cell lines. The efficiency of the knock-out is determined by analyzing mRNA levels using lightcycler quantification. The oligomers that resulted in the highest level of transcript knock-out, wherein the level was at least about 50%, preferably about 80-90%, up to 95% or more up to undetectable message, are selected for use in a cell-based proliferation assay, an anchorage independent growth assay, and an apoptosis assay.

The ability of each designed antisense oligonucleotide to inhibit gene expression is tested through transfection into SW620 colon carcinoma cells. For each transfection mixture, a carrier molecule (such as a lipid, lipid derivative, lipid-like molecule, cholesterol, cholesterol derivative, or cholesterol-like molecule) is prepared to a working concentration of 0.5 mM in water, sonicated to yield a uniform solution, and filtered through a 0.45 μm PVDF membrane. The antisense or control oligonucleotide is then prepared to a working concentration of 100 μM in sterile Millipore water. The oligonucleotide is further diluted in OptiMEM™ (Gibco/BRL), in a microfuge tube, to 2 μM, or approximately 20 μg oligo/ml of OptiMEM™. In a separate microfuge tube, the carrier molecule, typically in the amount of about 1.5-2 nmol carrier/μg antisense oligonucleotide, is diluted into the same volume of OptiMEM™ used to dilute the oligonucleotide. The diluted antisense oligonucleotide is immediately added to the diluted carrier and mixed by pipetting up and down. Oligonucleotide is added to the cells to a final concentration of 30 nM.

The level of target mRNA that corresponds to a target gene of interest in the transfected cells is quantitated in the cancer cell lines using the Roche LightCycler™ real-time PCR machine. Values for the target mRNA are normalized versus an internal control (e.g., beta-actin). For each 20 μl reaction, extracted RNA (generally 0.2-1 μg total) is placed into a sterile 0.5 or 1.5 ml microcentrifuge tube, and water is added to a total volume of 12.5 μl. To each tube is added 7.5 μl of a buffer/enzyme mixture, prepared by mixing (in the order listed) 2.5 μl H₂O, 2.0 μl 10× reaction buffer, 10 μl oligo dT (20 pmol), 1.0 μl dNTP mix (10 mM each), 0.5 μl RNAsin® (20 u) (Ambion, Inc., Hialeah, Fla.), and 0.5 μl MMLV reverse transcriptase (50 u) (Ambion, Inc.). The contents are mixed by pipetting up and down, and the reaction mixture is incubated at 42° C. for 1 hour. The contents of each tube are centrifuged prior to amplification.

An amplification mixture is prepared by mixing in the following order: 1× PCR buffer II, 3 mM MgCl₂, 140 μM each dNTP, 0.175 pmol each oligo, 1:50,000 dil of SYBR® Green, 0.25 mg/ml BSA, 1 unit Taq polymerase, and H₂O to 20 μl. (PCR buffer II is available in 10× concentration from Perkin-Elmer, Norwalk, Conn. ). In 1× concentration it contains 10 mM Tris pH 8.3 and 50 mM KCl. SYBR® Green (Molecular Probes, Eugene, Oreg.) is a dye which fluoresces when bound to double stranded DNA. As double stranded PCR product is produced during amplification, the fluorescence from SYBR® Green increases. To each 20 μl aliquot of amplification mixture, 2 μl of template RT is added, and amplification is carried out according to standard protocols. The results are expressed as the percent decrease in expression of the corresponding gene product relative to non-transfected cells, vehicle-only transfected (mock-transfected) cells, or cells transfected with reverse control oligonucleotides.

Example 52 Effect of Expression on Proliferation

The effect of gene expression on the inhibition of cell proliferation can be assessed in metastatic breast cancer cell lines (MDA-MB-231 (“231”)); SW620 colon colorectal carcinoma cells; SKOV3 cells (a human ovarian carcinoma cell line); or LNCaP, PC3, 22Rv1, MDA-PCA-2b, or DU145 prostate cancer cells.

Cells are plated to approximately 60-80% confluency in 96-well dishes. Antisense or reverse control oligonucleotide is diluted to 2 μM in OptiMEM™. The oligonucleotide-OptiMEM™ can then be added to a delivery vehicle, which delivery vehicle can be selected so as to be optimized for the particular cell type to be used in the assay. The oligo/delivery vehicle mixture is then further diluted into medium with serum on the cells. The final concentration of oligonucleotide for all experiments can be about 300 nM.

Antisense oligonucleotides are prepared as described above (see Example 51). Cells are transfected overnight at 37° C. and the transfection mixture is replaced with fresh medium the next morning. Transfection is carried out as described above in Example 51.

Those antisense oligonucleotides that result in inhibition of proliferation of SW620 cells indicate that the corresponding gene plays a role in production or maintenance of the cancerous phenotype in cancerous colon cells. Those antisense oligonucleotides that inhibit proliferation in SKOV3 cells represent genes that play a role in production or maintenance of the cancerous phenotype in cancerous breast cells. Those antisense oligonucleotides that result in inhibition of proliferation of MDA-MB-231 cells indicate that the corresponding gene plays a role in production or maintenance of the cancerous phenotype in cancerous ovarian cells. Those antisense oligonucleotides that inhibit proliferation in LNCaP, PC3, 22Rv1, MDA-PCA-2b, or DU145 cells represent genes that play a role in production or maintenance of the cancerous phenotype in cancerous prostate cells.

Example 53 Effect of Gene Expression on Cell Migration

The effect of gene expression on the inhibition of cell migration can be assessed in SW620 colon cancer cells using static endothelial cell binding assays, non-static endothelial cell binding assays, and transmigration assays.

For the static endothelial cell binding assay, antisense oligonucleotides are prepared as described above (see Example 51). Two days prior to use, colon cancer cells (CaP) are plated and transfected with antisense oligonucleotide as described above (see Examples 51 and 52). On the day before use, the medium is replaced with fresh medium, and on the day of use, the medium is replaced with fresh medium containing 2 μM CellTracker green CMFDA (Molecular Probes, Inc.) and cells are incubated for 30 min. Following incubation, CaP medium is replaced with fresh medium (no CMFDA) and cells are incubated for an additional 30-60 min. CaP cells are detached using CMF PBS/2.5 mM EDTA or trypsin, spun and resuspended in DMEM/1% BSA/10 mM HEPES pH 7.0. Finally, CaP cells are counted and resuspended at a concentration of 1×10⁶ cells/ml.

Endothelial cells (EC) are plated onto 96-well plates at 40-50% confluence 3 days prior to use. On the day of use, EC are washed 1× with PBS and 506 DMDM/1%BSA/10 mM HEPES pH 7 is added to each well. To each well is then added 50K (50λ) CaP cells in DMEM/1% BSA/10 mM HEPES pH 7. The plates are incubated for an additional 30 min and washed 5× with PBS containing Ca⁺⁺ and Mg⁺⁺. After the final wash, 100 μL PBS is added to each well and fluorescence is read on a fluorescent plate reader (Ab492/Em 516 nm).

For the non-static endothelial cell binding assay, CaP are prepared as described above. EC are plated onto 24-well plates at 30-40% confluence 3 days prior to use. On the day of use, a subset of EC are treated with cytokine for 6 hours then washed 2× with PBS. To each well is then added 150-200K CaP cells in DMEM/1% BSA/10 mM HEPES pH 7. Plates are placed on a rotating shaker (70 RPM) for 30 min and then washed 3× with PBS containing Ca⁺⁺ and Mg⁺⁺. After the final wash, 500 μL PBS is added to each well and fluorescence is read on a fluorescent plate reader (Ab492/Em 516 nm).

For the transmigration assay, CaP are prepared as described above with the following changes. On the day of use, CaP medium is replaced with fresh medium containing 5 μM CellTracker green CMFDA (Molecular Probes, Inc.) and cells are incubated for 30 min. Following incubation, CaP medium is replaced with fresh medium (no CMFDA) and cells are incubated for an additional 30-60 min. CaP cells are detached using CMF PBS/2.5 mM EDTA or trypsin, spun and resuspended in EGM-2-MV medium. Finally, CaP cells are counted and resuspended at a concentration of 1×10⁶ cells/ml.

EC are plated onto FluorBlok transwells (BD Biosciences) at 30-40% confluence 5-7 days before use. Medium is replaced with fresh medium 3 days before use and on the day of use. To each transwell is then added 50K labeled CaP. 30 min prior to the first fluorescence reading, 10 μg of FITC-dextran (10K MW) is added to the EC plated filter. Fluorescence is then read at multiple time points on a fluorescent plate reader (Ab492/Em 516 nm).

Those antisense oligonucleotides that result in inhibition of binding of SW620 colon cancer cells to endothelial cells indicate that the corresponding gene plays a role in the production or maintenance of the cancerous phenotype in cancerous colon cells. Those antisense oligonucleotides that result in inhibition of endothelial cell transmigration by SW620 colon cancer cells indicate that the corresponding gene plays a role in the production or maintenance of the cancerous phenotype in cancerous colon cells.

Example 54 Effect of Gene Expression on Colony Formation

The effect of gene expression upon colony formation of SW620 cells, SKOV3 cells, MD-MBA-231 cells, LNCaP cells, PC3 cells, 22Rv1 cells, MDA-PCA-2b cells, and DU145 cells can be tested in a soft agar assay. Soft agar assays are conducted by first establishing a bottom layer of 2 ml of 0.6% agar in media plated fresh within a few hours of layering on the cells. The cell layer is formed on the bottom layer by removing cells transfected as described above from plates using 0.05% trypsin and washing twice in media. The cells are counted in a Coulter counter, and resuspended to 106 per ml in media. 10 μl aliquots are placed with media in 96-well plates (to check counting with WST1), or diluted further for the soft agar assay. 2000 cells are plated in 800 μl 0.4% agar in duplicate wells above 0.6% agar bottom layer. After the cell layer agar solidifies, 2 ml of media is dribbled on top and antisense or reverse control oligo (produced as described in Example 51) is added without delivery vehicles. Fresh media and oligos are added every 3-4 days. Colonies form in 10 days to 3 weeks. Fields of colonies are counted by eye. Wst-1 metabolism values can be used to compensate for small differences in starting cell number. Larger fields can be scanned for visual record of differences.

Those antisense oligonucleotides that result in inhibition of colony formation of SW620 cells indicate that the corresponding gene plays a role in production or maintenance of the cancerous phenotype in cancerous colon cells. Those antisense oligonucleotides that inhibit colony formation in SKOV3 cells represent genes that play a role in production or maintenance of the cancerous phenotype in cancerous breast cells. Those antisense oligonucleotides that result in inhibition of colony formation of MDA-MB-231 cells indicate that the corresponding gene plays a role in production or maintenance of the cancerous phenotype in cancerous ovarian cells. Those antisense oligonucleotides that inhibit colony formation in LNCaP, PC3, 22Rv1, MDA-PCA-2b, or DU145 cells represent genes that play a role in production or maintenance of the cancerous phenotype in cancerous prostate cells.

Example 55 Induction of Cell Death Upon Depletion of Polypeptides by Depletion of mRNA (“Antisense Knockout”)

In order to assess the effect of depletion of a target message upon cell death, SW620 cells, or other cells derived from a cancer of interest, can be transfected for proliferation assays. For cytotoxic effect in the presence of cisplatin (cis), the same protocol is followed but cells are left in the presence of 2 μM drug. Each day, cytotoxicity is monitored by measuring the amount of LDH enzyme released in the medium due to membrane damage. The activity of LDH is measured using the Cytotoxicity Detection Kit from Roche Molecular Biochemicals. The data is provided as a ratio of LDH released in the medium vs. the total LDH present in the well at the same time point and treatment (rLDH/tLDH). A positive control using antisense and reverse control oligonucleotides for BCL2 (a known anti-apoptotic gene) is included; loss of message for BCL2 leads to an increase in cell death compared with treatment with the control oligonucleotide (background cytotoxicity due to transfection).

Example 56 Functional Analysis of Gene Products Differentially Expressed in Colon Cancer in Patients

The gene products of sequences of a gene differentially expressed in cancerous cells can be further analyzed to confirm the role and function of the gene product in tumorigenesis, e.g., in promoting or inhibiting development of a metastatic phenotype. For example, the function of gene products corresponding to genes identified herein can be assessed by blocking function of the gene products in the cell. For example, where the gene product is secreted or associated with a cell surface membrane, blocking antibodies can be generated and added to cells to examine the effect upon the cell phenotype in the context of, for example, the transformation of the cell to a cancerous, particularly a metastatic, phenotype. In order to generate antibodies, a clone corresponding to a selected gene product is selected, and a sequence that represents a partial or complete coding sequence is obtained. The resulting clone is expressed, the polypeptide produced isolated, and antibodies generated. The antibodies are then combined with cells and the effect upon tumorigenesis assessed.

Where the gene product of the differentially expressed genes identified herein exhibits sequence homology to a protein of known function (e.g., to a specific kinase or protease) and/or to a protein family of known function (e.g., contains a domain or other consensus sequence present in a protease family or in a kinase family), then the role of the gene product in tumorigenesis, as well as the activity of the gene product, can be examined using small molecules that inhibit or enhance function of the corresponding protein or protein family.

Additional functional assays include, but are not necessarily limited to, those that analyze the effect of expression of the corresponding gene upon cell cycle and cell migration. Methods for performing such assays are well known in the art.

Example 57 Contig Assembly and Addition Gene Characterization

The sequences of the polynucleotides provided in the present invention can be used to extend the sequence information of the gene to which the polynucleotides correspond (e.g., a gene, or mRNA encoded by the gene, having a sequence of the polynucleotide described herein). This expanded sequence information can in turn be used to further characterize the corresponding gene, which in turn provides additional information about the nature of the gene product (e.g., the normal function of the gene product). The additional information can serve to provide additional evidence of the gene product's use as a therapeutic target, and provide further guidance as to the types of agents that can modulate its activity.

In one example, a contig is assembled using a sequence of a polynucleotide of the present invention, which is present in a clone. A “contig” is a contiguous sequence of nucleotides that is assembled from nucleic acid sequences having overlapping (e.g., shared or substantially similar) sequence information. The sequences of publicly-available ESTs (Expressed Sequence Tags) and the sequences of various clones from several cDNA libraries synthesized at Chiron can be used in the contig assembly.

The contig is assembled using the software program Sequencher, version 4.05, according to the manufacturer's instructions and an overview alignment of the contiged sequences is produced. The sequence information obtained in the contig assembly can then be used to obtain a consensus sequence derived from the contig using the Sequencher program. The consensus sequence is used as a query sequence in a TeraBLASTN search of the DGTI DoubleTwist Gene Index (DoubleTwist, Inc., Oakland, Calif.), which contains all the EST and non-redundant sequence in public databases.

Through contig assembly and the use of homology searching software programs, the sequence information provided herein can be readily extended to confirm, or confirm a predicted, gene having the sequence of the polynucleotides described in the present invention. Further the information obtained can be used to identify the function of the gene product of the gene corresponding to the polynucleotides described herein. While not necessary to the practice of the invention, identification of the function of the corresponding gene, can provide guidance in the design of therapeutics that target the gene to modulate its activity and modulate the cancerous phenotype (e.g., inhibit metastasis, proliferation, and the like).

Example 58 Source of biological Materials

The biological materials used in the experiments that led to the present invention are described below.

Source of Patient Tissue Samples

Normal and cancerous tissues were collected from patients using laser capture microdissection (LCM) techniques, which techniques are well known in the art (see, e.g., Ohyama et al. (2000) Biotechniques 29:530-6; Curran et al. (2000) Mol. Pathol. 53:64-8; Suarez-Quian et al. (1999) Biotechniques 26:328-35; Simone et al. (1998) Trends Genet 14:272-6; Conia et al. (1997) J. Clin. Lab. Anal. 11:28-38; Emmert-Buck et al. (1996) Science 274:998-1001). Table 32 provides information about each patient from which colon tissue samples were isolated, including: the Patient ID (“PT ID”) and Path ReportID (“Path ID”), which are numbers assigned to the patient and the pathology reports for identification purposes; the group (“Grp”) to which the patients have been assigned; the anatomical location of the tumor (“Anatom Loc”); the primary tumor size (“Size”); the primary tumor grade (“Grade”); the identification of the histopathological grade (“Histo Grade”); a description of local sites to which the tumor had invaded (“Local Invasion”); the presence of lymph node metastases (“Lymph Met”); the incidence of lymph node metastases (provided as a number of lymph nodes positive for metastasis over the number of lymph nodes examined) (“Lymph Met Incid”); the regional lymphnode grade (“Reg Lymph Grade”); the identification or detection of metastases to sites distant to the tumor and their location (“Dist Met & Loc”); the grade of distant metastasis (“Dist Met Grade”); and general comments about the patient or the tumor (“Comments”). Histopathology of all primary tumors indicated the tumor was adenocarcinoma except for Patient ID Nos. 130 (for which no information was provided), 392 (in which greater than 50% of the cells were mucinous carcinoma), and 784 (adenosquamous carcinoma). Extranodal extensions were described in three patients, Patient ID Nos. 784, 789, and 791. Lymphovascular invasion was described in Patient ID Nos. 128, 228, 278, 517, 534, 784, 786, 789, 791, 890, and 892. Crohn's-like infiltrates were described in seven patients, Patient ID Nos. 52, 264, 268, 392, 393, 784, and 791. TABLE 32 Lymph Reg Dist Path Anatom Histo Lymph Met Lymph Dist Met Met Pt ID ID Grp Loc Size Grade Grade Local Invasion Met Incid Grade & Loc Grade Comment 10 16 III Cecum 8.5 T3 G2 through Pos 1/17 N1 Neg M0 Moderately muscularis propria differentiated approaching pericolic fat, but not at serosal surface 15 21 III Ascending 4.0 T3 G2 Extending into Pos 3/8 N1 Neg MX invasive colon subserosal adipose adeno- tissue carcinoma, moderately differentiated; focal perineural invasion is seen 52 71 II Cecum 9.0 T3 G3 Invasion through Neg 0/12 N0 Neg M0 Hyperplastic muscularis polyp in propria, subserosal appendix. involvement; ileocec. valve involvement 121 140 II Sigmoid 6 T4 G2 Invasion of Neg 0/34 N0 Neg M0 Perineural muscularis propria invasion; donut into serosa, anastomosis involving Neg. One submucosa of tubulovillous urinary bladder and one tubular adenoma with no high grade dysplasia. 125 144 II Cecum 6 T3 G2 Invasion through Neg 0/19 N0 Neg M0 patient history the muscularis of metastatic propria into melanoma suserosal adipose tissue. Ileocecal junction. 128 147 III Transverse 5.0 T3 G2 Invasion of Pos 1/5 N1 Neg M0 colon muscularis propria into percolonic fat 130 149 Splenic 5.5 T3 through wall and Pos 10/24 N2 Neg M1 flexure into surrounding adipose tissue 133 152 II Rectum 5.0 T3 G2 Invasion through Neg 0/9 N0 Neg M0 Small separate muscularis propria tubular into non- adenoma peritonealized (0.4 cm) pericolic tissue; gross configuration is annular. 141 160 IV Cecum 5.5 T3 G2 Invasion of Pos 7/21 N2 Pos - M1 Perineural muscularis propria Liver invasion into pericolonic identified adipose tissue, but adjacent to not through serosa. metastatic Arising from adeno- tubular adenoma. carcinoma. 156 175 III Hepatic 3.8 T3 G2 Invasion through Pos 2/13 N1 Neg M0 Separate flexure mucsularis propria tubolovillous into and tubular subserosa/pericolic adenomas adipose, no serosal involvement. Gross configuration annular. 228 247 III Rectum 5.8 T3 G2 to Invasion through Pos 1/8 N1 Neg MX Hyperplastic G3 muscularis propria polyps to involve subserosal, perirectoal adipose, and serosa 264 283 II Ascending 5.5 T3 G2 Invasion through Neg 0/10 N0 Neg M0 Tubulovillous colon muscularis propria adenoma with into subserosal high grade adipose tissue. dysplasia 266 285 III Transverse 9 T3 G2 Invades through Neg 0/15 N1 Pos - MX colon muscularis propria Me- to involve senteric pericolonic deposit adipose, extends to serosa. 267 286 III Ileocecal 4.5 T2 G2 Confined to Pos 2/12 N1 Neg M0 muscularis propria 268 287 I Cecum 6.5 T2 G2 Invades full Neg 0/12 N0 Neg M0 thickness of muscularis propria, but mesenteric adipose free of malignancy 278 297 III Rectum 4 T3 G2 Invasion into Pos 7/10 N2 Neg M0 Descending perirectal adipose colon polyps, tissue. no HGD or carcinoma identified . . . 295 314 II Ascending 5.0 T3 G2 Invasion through Neg 0/12 N0 Neg M0 Melanosis coli colon muscularis propria and diverticular into percolic disease. adipose tissue. 296 315 III Cecum 5.5 T3 G2 Invasion through Pos 2/12 N1 Neg M0 Tubulovillous muscularis propria adenoma and invades (2.0 cm) pericolic adipose with no tissue. Ileocecal high grade junction. dysplasia. Neg. liver biopsy. 300 319 III De- 5.2 T2 G2 through the Pos 2/2 N1 Neg M0 scending muscularis propria colon into pericolic fat 322 341 II Sigmoid 7 T3 G2 through the Neg 0/5 N0 Neg M0 vascular muscularis propria invasion is into pericolic fat identified 339 358 II Recto- 6 T3 G2 Extends into Neg 0/6 N0 Neg M0 1 hyperplastic sigmoid perirectal fat but polyp identified does not reach serosa 341 360 II Ascending 2 cm T3 G2 Invasion through Neg 0/4 N0 Neg MX colon invasive muscularis propria to involve pericolonic fat. Arising from villous adenoma. 356 375 II Sigmoid 6.5 T3 G2 Through colon Neg 0/4 N0 Neg M0 wall into subserosal adipose tissue. No serosal spread seen. 360 412 III Ascending 4.3 T3 G2 Invasion thru Pos 1/5 N1 Neg M0 Two mucosal colon muscularis propria polyps to pericolonic fat 392 444 IV Ascending 2 T3 G2 Invasion through Pos 1/6 N1 Pos - M1 Tumor arising colon muscularis propria Liver at prior into subserosal ileocolic adipose tissue, not surgical serosa. anastomosis. 393 445 II Cecum 6.0 T3 G2 Cecum, invades Neg 0/21 N0 Neg M0 through muscularis propria to involve subserosal adipose tissue but not serosa. 413 465 IV Cecum 4.8 T3 G2 Invasive through Neg 0/7 N0 Pos - M1 rediagnosis of muscularis to Liver oophorectomy involve periserosal path to fat; abutting metastatic ileocecal junction. colon cancer. 452 504 II Ascending 4 T3 G2 through Neg 0/39 N0 Neg M0 colon muscularis propria approaching pericolic fat, but not at serosal surface 505 383 IV 7.5 T3 G2 Invasion through Pos 2/17 N1 Pos - M1 Anatomical muscularis propria Liver location of involving pericolic primary not adipose, serosal notated in surface uninvolved report. Evidence of chronic colitis. 517 395 IV Sigmoid 3 T3 G2 penetrates Pos 6/6 N2 Neg M0 No mention of muscularis distant met in propria, involves report pericolonic fat. 534 553 II Ascending 12 T3 G3 Invasion through Neg 0/8 N0 Neg M0 Omentum with colon the muscularis fibrosis and fat propria involving necrosis. Small pericolic fat. bowel with Serosa free of acute and tumor. chronic serositis, focal abscess and adhesions. 546 565 IV Ascending 5.5 T3 G2 Invasion through Pos 6/12 N2 Pos - M1 colon muscularis propria Liver extensively through submucosal and extending to serosa. 577 596 II Cecum 11.5 T3 G2 Invasion through Neg 0/58 N0 Neg M0 Appendix the bowel wall, dilated and into suberosal fibrotic, but not adipose. Serosal involved by surface free of tumor tumor. 695 714 II Cecum 14.0 T3 G2 extending through Neg 0/22 N0 Neg MX moderately bowel wall into differentiated serosal fat adeno- carcinoma with mucinous diferentiation (% not stated), tubular adenoma and hyperplstic polyps present, 784 803 IV Ascending 3.5 T3 G3 through Pos 5/17 N2 Pos - M1 invasive poorly colon muscularis propria Liver differentiated into pericolic soft adenosquamous tissues carcinoma 786 805 IV De- 9.5 T3 G2 through Neg 0/12 N0 Pos - M1 moderately scending muscularis propria Liver differentiated colon into pericolic fat, invasive but not at serosal adeno- surface carcinoma 787 806 II Recto- 2.5 T3 G2-G3 Invasion of Neg N0 Neg MX Peritumoral sigmoid muscularis propria lymphocytic into soft tissue response; 5 LN examined in pericolic fat, no metastatases observed. 789 808 IV Cecum 5.0 T3 G2-G3 Extending through Pos 5/10 N2 Pos - M1 Three muscularis propria Liver fungating into pericolonic fat lesions examined. 790 809 IV Rectum 6.8 T3 G1-G2 Invading through Pos 3/13 N1 Pos - M1 muscularis propria Liver into perirectal fat 791 810 IV Ascending 5.8 T3 G3 Through the Pos 13/25 N2 Pos - M1 poorly colon muscularis propria Liver differentiated into pericolic fat invasive colonic adeno- carcinoma 888 908 IV Ascending 2.0 T2 G1 Into muscularis Pos 3/21 N0 Pos - M1 well to colon propria Liver moderately differentiated adeno- carcinomas; this patient has tumors of the ascending colon and the sigmoid colon 889 909 IV Cecum 4.8 T3 G2 Through Pos 1/4 N1 Pos - M1 moderately muscularis propria Liver differentiated int subserosal adeno- tissue carcinoma 890 910 IV Ascending T3 G2 Through Pos 11/15 N2 Pos - M1 colon muscularis propria Liver into subserosa. 891 911 IV Rectum 5.2 T3 G2 Invasion through Pos 4/15 N2 Pos - M1 Perineural muscularis propria Liver invasion into perirectal soft present. tissue 892 912 IV Sigmoid 5.0 T3 G2 Invasion into Pos 1/28 N1 Pos - M1 Perineural pericolic sort Liver, left invasion tissue. Tumor and right present, focally invading lobe, extensive. skeletal muscle omentum Patient with a attached to colon. history of colon cancer. 893 913 IV Transverse 6.0 T3 G2-G3 Through Pos 14/17 N2 Pos - M1 Perineural colon muscularis propria Liver invasion into pericolic fat focally present. Omentum mass, but resection with no tumor identified. 989 1009 IV Sigmoid 6.0 T3 G2 Invasion through Pos 1/7 N1 Pos - M1 Primary colon wall and Liver adeno- focally involving carcinoma subserosal tissue. arising from tubulovillous adenoma.

Two overlapping groups of patients described in Table 32 were studied. The first group contained 33 members whereas the second group contained 22 members. In the case of the first group of patients, gene product expression profiles of tissue samples from metastasized tumors were compared to gene product expression profiles of an “unmatched” sample, where the unmatched sample is a pool of samples of normal colon from the sample patients. For the second group of patients, gene product expression profiles of tissue samples from metastasized tumors were compared to gene product expression profiles of a “matched” sample, where the matched sample is matched to a single sample within a patient. As such, a metastasized colon tumor sample is “matched” with a normal colon sample or a primary colon tumor from the same patient. Metastases of colon cancers may appear in any tissue, including bone, breast, lung, liver, brain, kidney skin, intestine, appendix, etc. In many patients, the colon cancer had metastasized to liver.

Source of Polynucleotides on Arrays

Polynucleotides for use on the arrays were obtained from both publicly available sources and from cDNA libraries generated from selected cell lines and patient tissues. Table 33 provides information about the polynucleotides on the arrays including: (1) the “SEQ ID NO” assigned to each sequence for use in the present specification; (2) the spot identification number (“Spot ID”), an internal reference that serves as a unique identifier for the spot on the array; (3) the “Clone ID” assigned to the clone from which the sequence was isolated; and (4) the “MAClone ID” assigned to the clone from which the sequence was isolated. The sequences corresponding to the SEQ ID NOS are provided in the Sequence Listing.

Characterization of Sequences

The sequences of the isolated polynucleotides were first masked to eliminate low complexity sequences using the RepeatMasker masking program, publicly available through a web site supported by the University of Washington (See also Smit, A. F. A. and Green, P., unpublished results). Generally, masking does not influence the final search results, except to eliminate sequences of relatively little interest due to their low complexity, and to eliminate multiple “hits” based on similarity to repetitive regions common to multiple sequences, e.g., Alu repeats. Masking resulted in the elimination of several sequences.

The remaining sequences of the isolated polynucleotides were used in a homology search of the GenBank database using the TeraBLAST program (TimeLogic, Crystal Bay, Nev.), a DNA and protein sequence homology searching algorithm. TeraBLAST is a version of the publicly available BLAST search algorithm developed by the National Center for Biotechnology, modified to operate at an accelerated speed with increased sensitivity on a specialized computer hardware platform. The program was run with the default parameters recommended by TimeLogic to provide the best sensitivity and speed for searching DNA and protein sequences. Gene assignment for the query sequences was determined based on best hit from the GenBank database; expectancy values are provided with the hit.

Summary of TeraBLAST Search Results

Table 34 provides information about the gene corresponding to each polynucleotide. Table 34 includes: (1) the “SEQ ID NO” of the sequence; (2) the “Clone ID” assigned to the clone from which the sequence was isolated; (3) the “MAClone ID” assigned to the clone from which the sequence was isolated; (4) the library source of the clone (“PatientType”) (5) the GenBank Accession Number of the publicly available sequence corresponding to the polynucleotide (“GBHit”); (6) a description of the GenBank sequence (“GBDescription”); and (7) the score of the similarity of the polynucleotide sequence and the GenBank sequence (“GBScore”). The published information for each GenBank and EST description, as well as the corresponding sequence identified by the provided accession number, are incorporated herein by reference.

Example 59 detection of Differential Expression Using Arrays

cDNA probes were prepared from total RNA isolated from the patient samples described above. Since LCM provides for the isolation of specific cell types to provide a substantially homogenous cell sample, this provided for a similarly pure RNA sample.

Total RNA was first reverse transcribed into cDNA using a primer containing a T7 RNA polymerase promoter, followed by second strand DNA synthesis. cDNA was then transcribed in vitro to produce antisense RNA using the T7 promoter-mediated expression (see, e.g., Luo et al. (1999) Nature Med 5:117-122), and the antisense RNA was then converted into cDNA. The second set of cDNAs were again transcribed in vitro, using the T7 promoter, to provide antisense RNA. Optionally, the RNA was again converted into cDNA, allowing for up to a third round of T7-mediated amplification to produce more antisense RNA. Thus the procedure provided for two or three rounds of in vitro transcription to produce the final RNA used for fluorescent labeling.

Fluorescent probes were generated by first adding control RNA to the antisense RNA mix, and producing fluorescently labeled cDNA from the RNA starting material. Fluorescently labeled cDNAs prepared from the tumor RNA sample were compared to fluorescently labeled cDNAs prepared from a normal cell RNA sample. For example, the cDNA probes from the normal cells were labeled with Cy3 fluorescent dye (green) and the cDNA probes prepared from the tumor cells were labeled with Cy5 fluorescent dye (red), and vice versa.

Each array used had an identical spatial layout and control spot set. Each microarray was divided into two areas, each area having an array with, on each half, twelve groupings of 32×12 spots, for a total of about 9,216 spots on each array. The two areas are spotted identically which provides for at least two duplicates of each clone per array.

Polynucleotides for use on the arrays were obtained from both publicly available sources and from cDNA libraries generated from selected cell lines and patient tissues as described above and in Table 33. PCR products of from about 0.5 kb to 2.0 kb amplified from these sources were spotted onto the array using a Molecular Dynamics Gen III spotter according to the manufacturer's recommendations. The first row of each of the 24 regions on the array had about 32 control spots, including 4 negative control spots and 8 test polynucleotides. The test polynucleotides were spiked into each sample before the labeling reaction with a range of concentrations from 2-600 pg/slide and ratios of 1:1. For each array design, two slides were hybridized with the test samples reverse-labeled in the labeling reaction. This provided for about four duplicate measurements for each clone, two of one color and two of the other, for each sample.

The differential expression assay was performed by mixing equal amounts of probes from matched or unmatched samples. The arrays were pre-incubated for about 2 hrs at 60° C. in 5×SSC/0.2% SDS/1 mM EDTA, and then washed three times in water and twice in isopropanol. Following prehybridization of the array, the probe mixture was then hybridized to the array under conditions of high stringency (overnight at 42° C. in 50% formamide, 5×SSC, and 0.2% SDS. After hybridization, the array was washed at 55° C. three times as follows: 1) first wash in 1×SSC/0.2% SDS; 2) second wash in 0.1×SSC/0.2% SDS; and 3) third wash in 0.1×SSC.

The arrays were then scanned for green and red fluorescence using a Molecular Dynamics Generation III dual color laser-scanner/detector. The images were processed using BioDiscovery Au togene software, and the data from each scan set normalized to provide for a ratio of expression relative to normal. Data from the microarray experiments was analyzed according to the algorithms described in U.S. application Ser. No. 60/252,358, filed Nov. 20, 2000, by E. J. Moler, M. A. Boyle, and F. M. Randazzo, and entitled “Precision and accuracy in cDNA microarray data,” which application is specifically incorporated herein by reference.

The experiment was repeated, this time labeling the two probes with the opposite color in order to perform the assay in both “color directions.” Each experiment was sometimes repeated with two more slides (one in each color direction). The level of fluorescence for each sequence on the array expressed as a ratio of the geometric mean of 8 replicate spots/genes from the four arrays or 4 replicate spots/gene from 2 arrays or some other permutation. The data were normalized using the spiked positive controls present in each duplicated area, and the precision of this normalization was included in the final determination of the significance of each differential. The fluorescent intensity of each spot was also compared to the negative controls in each duplicated area to determine which spots have detected significant expression levels in each sample.

A statistical analysis of the fluorescent intensities was applied to each set of duplicate spots to assess the precision and significance of each differential measurement, resulting in a p-value testing the null hypothesis that there is no differential in the expression level between the tumor and normal samples of each patient. During initial analysis of the microarrays, the hypothesis was accepted if p>10⁻³, and the differential ratio was set to 1.000 for those spots. All other spots have a significant difference in expression between the matched or unmatched samples. If the tumor sample has detectable expression and the normal does not, the ratio is truncated at 1000 since the value for expression in the normal sample would be zero, and the ratio would not be a mathematically useful value (e.g., infinity). If the normal sample has detectable expression and the tumor does not, the ratio is truncated to 0.001, since the value for expression in the tumor sample would be zero and the ratio would not be a mathematically useful value. These latter two situations are referred to herein as “on/off.” Database tables were populated using a 95% confidence level (p>0.05).

Table 35 provides the results for gene products that were over- or under-expressed as determined by comparison of matched or unmatched pairs of samples isolated from the two patient groups described above. The results show data from three separate experiments using the same set of gene products, each identified by SEQ ID NO. The three experiments are: 1) a comparison of the gene expression profile of metastasized colon tumor tissue compared to unmatched normal colon tissue (“unmatched metastasis/normal”); 2) a comparison of the gene expression profile of metastasized colon tumor tissue compared to normal colon tissue from the same patient (“matched metastasis/normal”); and 3) a comparison of the gene expression profile of metastasized colon tumor tissue compared to primary tumor tissue from the same patient (“matched metastasis/tumor”). If samples are matched, they are both samples from a single patient. If samples are unmatched, one sample is obtained from a patient, and compared to pooled samples from many patients.

The results in Table 35 show the sequences that are induced by at least 2-fold or greater in the metastasized colon tumor samples relative to normal or primary tumor tissue samples in at least 20% of the patients tested, or gene products in which expression levels of the gene in metastasized colon tumor cells was less than or equal to ½ of the expression level in normal or primary tissue samples in at least 20% of the patients tested. Table 35 includes: (1) the “SEQ ID NO” of the sequence tested; (2) the “Clone ID” assigned to the clone from which the sequence was isolated; and (3) the “MAClone ID” assigned to the clone from which the sequence was isolated; (4) the percentage of patients tested in which expression levels (e.g., as message level) of a particular sequence was at least 2-fold greater in metastasized colon cancer tissue than in unmatched or matched colon tissue (“>=2×”); (5) the percentage of patients tested in which expression levels (e.g., as message level) of the gene was less than or equal to ½ of the expression level in matched or unmatched colon tissue (“<=half×”); and (6) the number of patients analyzed in each experiment (“Ratios”).

These data provide evidence that the genes represented by the polynucleotides having the indicated sequences are differentially expressed in colon cancer, particularly metastasized colon cancer, as compared to colon cancer primary tumors or normal non-cancerous colon tissue.

Example 60 Antisense Regulation of Gene Expression

The expression of the differentially expressed genes represented by the polynucleotides in the cancerous cells can be analyzed using antisense knockout technology to confirm the role and function of the gene product in tumorigenesis, e.g., in promoting a metastatic phenotype.

A number of different oligonucleotides complementary to the mRNA generated by the differentially expressed genes identified herein can be designed as potential antisense oligonucleotides, and tested for their ability to suppress expression of the genes. Sets of antisense oligoiners specific to each candidate target are designed using the sequences of the polynucleotides corresponding to a differentially expressed gene and the software program HYBsimulator Version 4 (available for Windows 95/Windows NT or for Power Macintosh, RNAture, Inc. 1003 Health Sciences Road, West, Irvine, Calif. 92612 USA). Factors that are considered when designing antisense oligonucleotides include: 1) the secondary structure of oligonucleotides; 2) the secondary structure of the target gene; 3) the specificity with no or minimum cross-hybridization to other expressed genes; 4) stability; 5) length and 6) terminal GC content. The antisense oligonucleotide is designed so that it will hybridize to its target sequence under conditions of high stringency at physiological temperatures (e.g., an optimal temperature for the cells in culture to provide for hybridization in the cell, e.g., about 37° C.), but with minimal formation of homodimers.

Using the sets of oligomers and the HYBsimulator program, three to ten antisense oligonucleotides and their reverse controls are designed and synthesized for each candidate mRNA transcript, which transcript is obtained from the gene corresponding to the target polynucleotide sequence of interest. Once synthesized and quantitated, the oligomers are screened for efficiency of a transcript knock-out in a panel of cancer cell lines. The efficiency of the knock-out is determined by analyzing mRNA levels using lightcycler quantification. The oligomers that resulted in the highest level of transcript knock-out, wherein the level was at least about 50%, preferably about 80-90%, up to 95% or more up to undetectable message, are selected for use in a cell-based proliferation assay, an anchorage independent growth assay, and an apoptosis assay.

The ability of each designed antisense oligonucleotide to inhibit gene expression is tested through transfection into SW620 colon carcinoma cells. For each transfection mixture, a carrier molecule (such as a lipid, lipid derivative, lipid-like molecule, cholesterol, cholesterol derivative, or cholesterol-like molecule) is prepared to a working concentration of 0.5 mM in water, sonicated to yield a uniform solution, and filtered through a 0.45 μm PVDF membrane. The antisense or control oligonucleotide is then prepared to a working concentration of 100 μM in sterile Millipore water. The oligonucleotide is further diluted in OptiMEM™ (Gibco/BRL), in a microfuge tube, to 2 μM, or approximately 20 μg oligo/ml of OptiMEM™. In a separate microfuge tube, the carrier molecule, typically in the amount of about 1.5-2 nmol carrier/μg antisense oligonucleotide, is diluted into the same volume of OptiMEM™ used to dilute the oligonucleotide. The diluted antisense oligonucleotide is immediately added to the diluted carrier and mixed by pipetting up and down. Oligonucleotide is-added to the cells to a final concentration of 30 nM.

The level of target mRNA that corresponds to a target gene of interest in the transfected cells is quantitated in the cancer cell lines using the Roche LightCyclerm real-time PCR machine. Values for the target mRNA are normalized versus an internal control (e.g., beta-actin). For each 20 μl reaction, extracted RNA (generally 0.2-1 μg total) is placed into a sterile 0.5 or 1.5 ml microcentrifuge tube, and water is added to a total volume of 12.5 μl. To each tube is added 7.5 μl of a buffer/enzyme mixture, prepared by mixing (in the order listed) 2.5 μl H₂O, 2.0 μl 10× reaction buffer, 10 μl oligo dT (20 pmol), 1.0 μl dNTP mix (10 mM each), 0.5 μl RNAsin® (20 u) (Ambion, Inc., Hialeah, Fla. ), and 0.5 μl MMLV reverse transcriptase (50 u) (Ambion, Inc.). The contents are mixed by pipetting up and down, and the reaction mixture is incubated at 42° C. for 1 hour. The contents of each tube are centrifuged prior to amplification.

An amplification mixture is prepared by mixing in the following order: 1× PCR buffer II, 3 mM MgCl₂, 140 μM each dNTP, 0.175 pmol each oligo, 1:50,000 dil of SYBR® Green, 0.25 mg/ml BSA, 1 unit Taq polymerase, and H₂O to 20 μl. (PCR buffer II is available in 10× concentration from Perkin-Elmer, Norwalk, Conn.). In 1× concentration it contains 10 mM Tris pH 8.3 and 50 mM KCl. SYBR® Green (Molecular Probes, Eugene, Oreg.) is a dye which fluoresces when bound to double stranded DNA. As double stranded PCR product is produced during amplification, the fluorescence from SYBR®) Green increases. To each 20 μl aliquot of amplification mixture, 2 μl of template RT is added, and amplification is carried out according to standard protocols. The results are expressed as the percent decrease in expression of the corresponding gene product relative to non-transfected cells, vehicle-only transfected (mock-transfected) cells, or cells transfected with reverse control oligonucleotides.

Example 61 Effect of Expression on Proliferation

The effect of gene expression on the inhibition of cell proliferation can be assessed in, for example, metastatic breast cancer cell lines (MDA-MB-231 (“231”)); SW620 colon colorectal carcinoma cells; SKOV3 cells (a human ovarian carcinoma cell line); or LNCaP, PC3, 22Rv1, MDA-PCA-2b, or DU145 prostate cancer cells.

Cells are plated to approximately 60-80% confluency in 96-well dishes. Antisense or reverse control oligonucleotide is diluted to 2 μM in OptiMEM™. The oligonucleotide-OptiMEM™ can then be added to a delivery vehicle, which delivery vehicle can be selected so as to be optimized for the particular cell type to be used in the assay. The oligo/delivery vehicle mixture is then further diluted into medium with serum on the cells. The final concentration of oligonucleotide for all experiments can be about 300 nM.

Antisense oligonucleotides are prepared as described above (see Example 60). Cells are transfected overnight at 37° C. and the transfection mixture is replaced with fresh medium the next morning. Transfection is carried out as described above in Example 60.

Those antisense oligonucleotides inhibit proliferation of SW620 cells indicate that the corresponding gene plays a role in production or maintenance of the cancerous phenotype in cancerous colon cells. Those antisense oligonucleotides that inhibit proliferation in SKOV3 cells represent genes that play a role in production or maintenance of the cancerous phenotype in cancerous breast cells. Those antisense oligonucleotides that result in inhibition of proliferation of MDA-MB-231 cells indicate that the corresponding gene plays a role in production or maintenance of the cancerous phenotype in cancerous ovarian cells. Those antisense oligonucleotides that inhibit proliferation in LNCaP, PC3, 22Rv1, MDA-PCA-2b, or DU145 cells represent genes that play a role in production or maintenance of the cancerous phenotype in cancerous prostate cells.

Example 62 Effect of Gene Expression on Cell Migration

The effect of gene expression on the inhibition of cell migration can be assessed in SW620 colon cancer cells using static endothelial cell binding assays, non-static endothelial cell binding assays, and transmigration assays.

For the static endothelial cell binding assay, antisense oligonucleotides are prepared as described above (see Example 60). Two days prior to use, colon cancer cells (CaP) are plated and transfected with antisense oligonucleotide as described above (see Examples 60 and 61). On the day before use, the medium is replaced with fresh medium, and on the day of use, the medium is replaced with fresh medium containing 2 μM CellTracker green CMFDA (Molecular Probes, Inc.) and cells are incubated for 30 min. Following incubation, CaP medium is replaced with fresh medium (no CMFDA) and cells are incubated for an additional 30-60 min. CaP cells are detached using CMF PBS/2.5 mM EDTA or trypsin, spun and resuspended in DMEM/1% BSA/10 mM HEPES pH 7.0. Finally, CaP cells are counted and resuspended at a concentration of 1×106 cells/mi.

Endothelial cells (EC) are plated onto 96-well plates at 40-50% confluence 3 days prior to use. On the day of use, EC-are washed 1× with PBS and 50λ DMDM/1% BSA/10 mM HEPES pH 7 is added to each well. To each well is then added 50K (50□) CaP cells in DMEM/1% BSA/10 mM HEPES pH 7. The plates are incubated for an additional 30 min and washed 5× with PBS containing Ca++ and Mg++. After the final wash, 100 μL PBS is added to each well and fluorescence is read on a fluorescent plate reader (Ab492/Em 516 nm).

For the non-static endothelial cell binding assay, CaP are prepared as described above. EC are plated onto 24-well plates at 30-40% confluence 3 days prior to use. On the day of use, a subset of EC are treated with cytokine for 6 hours then washed 2× with PBS. To each well is then added 150-200K CaP cells in DMEM/1% BSA/10 mM HEPES pH 7. Plates are placed on a rotating shaker (70 RPM) for 30 min and then washed 3× with PBS containing Ca++ and Mg++. After the final wash, 500 μL PBS is added to each well and fluorescence is read on a fluorescent plate reader (Ab492/Em 516 nm).

For the transmigration assay, CaP are prepared as described above with the following changes. On the day of use, CaP medium is replaced with fresh medium containing 5 μM CellTracker green CMFDA (Molecular Probes, Inc.) and cells are incubated for 30 min. Following incubation, CaP medium is replaced with fresh medium (no CMFDA) and cells are incubated for an additional 30-60 min. CaP cells are detached using CMF PBS/2.5 mM EDTA or trypsin, spun and resuspended in EGM-2-MV medium. Finally, CaP cells are counted and resuspended at a concentration of 1×106 cells/ml.

EC are plated onto FluorBlok transwells (BD Biosciences) at 30-40% confluence 5-7 days before use. Medium is replaced with fresh medium 3 days before use and on the day of use. To each transwell is then added 50K labeled CaP. 30 min prior to the first fluorescence reading, 10 μg of FITC-dextran (10K MW) is added to the EC plated filter. Fluorescence is then read at multiple time points on a fluorescent plate reader (Ab492/Em 516 nm).

Those antisense oligonucleotides that result in inhibition of binding of SW620 colon cancer cells to endothelial cells indicate that the corresponding gene plays a role in the production or maintenance of the cancerous phenotype in cancerous colon cells. Those antisense oligonucleotides that result in inhibition of endothelial cell transmigration by SW620 colon cancer cells indicate that the corresponding gene plays a role in the production or maintenance of the cancerous phenotype in cancerous colon cells.

Example 63 Effect of Gene Expression on Colony Formation

The effect of gene expression upon colony formation of SW620 cells, SKOV3 cells, MD-MBA-231 cells, LNCaP cells, PC3 cells, 22Rv1 cells, MDA-PCA-2b cells, and DU145 cells can be tested in a soft agar assay. Soft agar assays are conducted by first establishing a bottom layer of 2 ml of 0.6% agar in media plated fresh within a few hours of layering on the cells. The cell layer is formed on the bottom layer by removing cells transfected as described above from plates using 0.05% trypsin and washing twice in media. The cells are counted in a Coulter counter, and resuspended to 10⁶ per ml in media. 10 μl aliquots are placed with media in 96-well plates (to check counting with WST1), or diluted further for the soft agar assay. 2000 cells are plated in 800 μl 0.4% agar in duplicate wells above 0.6% agar bottom layer. After the cell layer agar solidifies, 2 ml of media is dribbled on top and antisense or reverse control oligo (produced as described in Example 60) is added without delivery vehicles. Fresh media and oligos are added every 3-4 days. Colonies form in 10 days to 3 weeks. Fields of colonies are counted by eye. WST-1 metabolism values can be used to compensate for small differences in starting cell number. Larger fields can be scanned for visual record of differences.

Those antisense oligonucleotides that result in inhibition of colony formation of SW620 cells indicate that the corresponding gene plays a role in production or maintenance of the cancerous phenotype in cancerous colon cells. Those antisense oligonucleotides that inhibit colony formation in SKOV3 cells represent genes that play a role in production or maintenance of the cancerous phenotype in cancerous breast cells. Those antisense oligonucleotides that result in inhibition of colony formation of MDA-MB-231 cells indicate that the corresponding gene plays a role in production or maintenance of the cancerous phenotype in cancerous ovarian cells. Those antisense oligonucleotides that inhibit colony formation in LNCaP, PC3, 22Rv1, MDA-PCA-2b, or DU145 cells represent genes that play a role in production or maintenance of the cancerous phenotype in cancerous prostate cells.

Example 64 Induction of Cell Death Upon Depletion of Polypeptides by Depletion of mRNA (“Antisense Knockout”)

In order to assess the effect of depletion of a target message upon cell death, SW620 cells, or other cells derived from a cancer of interest, can be transfected for proliferation assays. For cytotoxic effect in the presence of cisplatin (cis), the same protocol is followed but cells are left in the presence of 2 μM drug. Each day, cytotoxicity is monitored by measuring the amount of LDH enzyme released in the medium due to membrane damage. The activity of LDH is measured using the Cytotoxicity Detection Kit from Roche Molecular Biochemicals. The data is provided as a ratio of LDH released in the medium vs. the total LDH present in the well at the same time point and treatment (rLDH/tLDH). A positive control using antisense and reverse control oligonucleotides for BCL2 (a known anti-apoptotic gene) is included; loss of message for BCL2 leads to an increase in cell death compared with treatment with the control oligonucleotide (background cytotoxicity due to transfection).

Example 65 Reduction of Colon Cancer In Vivo

In order to assess the effect of depletion of a target message upon colon cancer metastasis and the growth of metastasized colon cancer cells in vivo, a mouse model is utilized. Mouse models for cancer metastasis are well known in the art (e.g. Hubbard et al Dis Colon Rectum. 2002 45:334-41; Rashidi et al Clin Cancer Res. 2000 6:2556-61; Rashidi et al Anticancer Res. 2000 20:715-22; Rho et al Anticancer Res. 1999 19:157-61; Hasegawa et al, Int J Cancer 1998 76-812-6; and Warren et al J Clin Invest. 1995 95:1789-97.

In one model, before, at the same time as, or sometime after the intravenous or intraperitoneal administration of cancer cells to a model mouse, antisense molecules of Example 60 or other inhibitory molecules are administered to the model mouse. Cancer progression, including establishment and growth of tumors derived from the administered cells and longevity of mice, are monitored.

Example 66 Functional Analysis of Gene Products Differentially Expressed in Colon Cancer in Patents

The gene products of sequences of a gene differentially expressed in cancerous cells can be further analyzed to confirm the role and function of the gene product in tumorigenesis, e.g., in promoting or inhibiting development of a metastatic phenotype. For example, the function of gene products corresponding to genes identified herein can be assessed by blocking function of the gene products in the cell. For example, where the gene product is secreted or associated with a cell surface membrane, blocking antibodies can be generated and added to cells to examine the effect upon the cell phenotype in the context of, for example, the transformation of the cell to a cancerous, particularly a metastatic, phenotype. In order to generate antibodies, a clone corresponding to a selected gene product is selected, and a sequence that represents a partial or complete coding sequence is obtained. The resulting clone is expressed, the polypeptide produced isolated, and antibodies generated. The antibodies are then combined with cells and the effect upon tumorigenesis assessed.

Where the gene product of the differentially expressed genes identified herein exhibits sequence homology to a protein of known function (e.g., to a specific kinase or protease) and/or to a protein family of known function (e.g., contains a domain or other consensus sequence present in a protease family or in a kinase family), then the role of the gene product in tumorigenesis, as well as the activity of the gene product, can be examined using small molecules that inhibit or enhance function of the corresponding protein or protein family.

Additional functional assays include, but are not necessarily limited to, those that analyze the effect of expression of the corresponding gene upon cell cycle and cell migration. Methods for performing such assays are well known in the art.

Example 67 Contig Assembly and Additional Gene Characterization

The sequences of the polynucleotides provided in the present invention can be used to extend the sequence information of the gene to which the polynucleotides correspond (e.g., a gene, or mRNA encoded by the gene, having a sequence of the polynucleotide described herein). This expanded sequence information can in turn be used to further characterize the corresponding gene, which in turn provides additional information about the nature of the gene product (e.g., the normal function of the gene product). The additional information can serve to provide additional evidence of the gene product's use as a therapeutic target, and provide further guidance as to the types of agents that can modulate its activity.

In one example, a contig is assembled using a sequence of a polynucleotide of the present invention, which is present in a clone. A “contig” is a contiguous sequence of nucleotides that is assembled from nucleic acid sequences having overlapping (e.g., shared or substantially similar) sequence information. The sequences of publicly-available ESTs (Expressed Sequence Tags) and the sequences of various clones from several cDNA libraries synthesized at Chiron can be used in the contig assembly.

The contig is assembled using the software program Sequencher, version 4.05, according to the manufacturer's instructions and an overview alignment of the contiged sequences is produced. The sequence information obtained in the contig assembly can then be used to obtain a consensus sequence derived from the contig using the Sequencher program. The consensus sequence is used as a query sequence in a TeraBLASTN search of the DGTI DoubleTwist Gene Index (DoubleTwist, Inc., Oakland, Calif.), which contains all the EST and non-redundant sequence in public databases.

Through contig assembly and the use of homology searching software programs, the sequence information provided herein can be readily extended to confirm, or confirm a predicted, gene having the sequence of the polynucleotides described in the present invention. Further the information obtained can be used to identify the function of the gene product of the gene corresponding to the polynucleotides described herein. While not necessary to the practice of the invention, identification of the function of the corresponding gene, can provide guidance in the design of therapeutics that target the gene to modulate its activity and modulate the cancerous phenotype (e.g., inhibit metastasis, proliferation, and the like).

While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto. 

1. A method for inhibiting a cancerous phenotype of a cell, said method comprising: contacting a cancerous mammalian cell with an agent for inhibition of a product of a gene identified by any of SEQ ID NOS:1-13996.
 2. The method of claim 1, wherein said cell is a breast cell.
 3. The method of claim 1, wherein said cancerous phenotype is aberrant cellular proliferation relative to a normal cell.
 4. The method of claim 1, wherein said cancerous phenotype is loss of contact inhibition of cell growth.
 5. The method of claim 1, wherein said agent is selected from the group consisting of a small molecule, an antibody, an antisense polynucleotide, and an RNAi molecule.
 6. The method of claim 1, wherein said inhibition is associated with a reduction in a level of protein encoded by a gene identified by any of SEQ ID NOS:1-13996.
 7. The method of claim 1, wherein said inhibition is associated with a reduction in a level of an RNA encoded by a gene identified by any of SEQ ID NOS:1-13996.
 8. The method of claim 1, wherein said inhibition is associated with a reduction in a level of activity of a protein encoded a gene identified by any of SEQ ID NOS:1-13996.
 9. A method for detecting a cancerous cell, said method comprising: detecting a level of a product of a gene identified by any of SEQ ID NOS:1-13996 or fragment thereof in a test sample obtained from a cell of a subject, comparing the level of said gene product to a control level of said gene prudoduct, wherein the presence of a cancerous cell is indicated by detection of said level and comparison to said control level.
 10. The method of claim 9, wherein said cancerous cell is a cancerous breast cell.
 11. The method of claim 9, wherein said gene product is nucleic acid.
 12. The method of claim 9, wherein said gene product is a polypeptide.
 13. The method of claim 9, wherein said detecting step uses a polymerase chain reaction.
 14. The method of claim 9, wherein said detecting step uses hybridization.
 15. The method of claim 9, wherein said sample is a sample of breast tissue.
 16. The method of claim 9, wherein said level of said product is indicative of the cancerous state of the cell of the test sample.
 17. A method of treating a subject with cancer, said method comprising: administering to a subject a pharmaceutically effective amount of an agent, wherein said agent modulates the activity of a product of a gene identified by any of SEQ ID NOS:1-13996.
 18. The method of claim 17, wherein said cancer is breast cancer.
 19. The method of claim 17, wherein said agent is selected from the group consisting of a small molecule, an antibody, an antisense polynucleotide, and an RNAi molecule.
 20. A method for assessing the tumor burden of a subject, said method comprising: detecting a level of a product of a gene identified by any of SEQ ID NOS:1-13996 in a test sample from a subject, wherein the level of said gene product in the test sample is indicative of the tumor burden in the subject.
 21. A method for identifying an agent that modulates a biological activity of a gene product differentially expressed in a cancerous cell as compared to a normal cell, said method comprising: contacting a candidate agent with a product of a gene identified by any of SEQ ID NOS:1-13996; and detecting modulation of a biological activity of said product relative to a level of biological activity in the absence of the candidate agent.
 22. The method of claim 21, wherein said cancerous cell and said normal cell are breast cells.
 23. The method of claim 21, wherein said detecting is by assessing expression of said gene product.
 24. The method of claim 23, wherein expression is assessed by detecting a polynucleotide gene product.
 25. The method of claim 23, wherein expression is assessed by detecting a polypeptide gene product.
 26. The method of claim 21, wherein said candidate agent is selected from the group consisting of a small molecule, an antibody, an antisense polynucleotide, and an RNAi molecule.
 27. The method of claim 21, wherein said biological activity is modulation of a cancerous phenotype.
 28. The method of claim 27, wherein said cancerous phenotype is abnormal cellular proliferation.
 29. The method of claim 27, wherein said cancerous phenotype is loss of contact inhibition. 